WO2003003984A2 - Novel proteins and nucleic acids encoding same - Google Patents

Abstract

Disclosed herein are nucleic acid sequences that encode novel polypeptides. Also disclosed are polypeptides encoded by these nucleic acid sequences, and antibodies, which immunospecifically-bind to the polypeptide, as well as derivatives, variants, mutants, or fragments of the aforementioned polypeptide, polynucleotide, or antibody. The invention further discloses therapeutic, diagnostic and research methods for diagnosis, treatment, and prevention of disorders involving anyone of these novel human nucleic acids and proteins.

Description

NOVEL PROTEINS AND NUCLEIC ACIDS ENCODING SAME

BACKGROUND OF THE INVENTION

The invention generally relates to nucleic acids and polypeptides. More particularly, the invention relates to nucleic acids encoding novel molecule (MOL) polypeptides, as well as vectors, host cells, antibodies, and recombinant methods for producing these nucleic acids and polypeptides.

SUMMARY OF THE INVENTION

The invention is based in part upon the discovery of nucleic acid sequences encoding novel polypeptides. The novel nucleic acids and polypeptides are referred to herein as MOLX, or MOL1, MOL2, MOL3, MOL4, MOL5, MOL6, MOL7, MOL8, MOL9, MOL10, MOL1 1, MOL12, MOL13, MOL14, MOL15, MOL16, MOL17, MOL18, MOL19, MOL20, MOL21, MOL22, and MOL23 nucleic acids and polypeptides. These nucleic acids and polypeptides, as well as derivatives, homologs, analogs and fragments thereof, will hereinafter be collectively designated as "MOLX" nucleic acid or polypeptide sequences.

In one aspect, the invention provides an isolated MOLX nucleic acid molecule encoding a MOLX polypeptide that includes a nucleic acid sequence that has identity to the nucleic acids disclosed in SEQ ID NOS: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 101 , 103, 105, 107, 109, 1 12, 1 15, 1 17, 1 19, 121, 124, 135, 137, 139, 141, 143, 145, 147, 149, 151, 153, 155, 157, 159, 161, 163, 165, and 166. In some embodiments, the MOLX nucleic acid molecule will hybridize under stringent conditions to a nucleic acid sequence complementary to a nucleic acid molecule that includes a protein-coding sequence of a MOLX nucleic acid sequence. The invention also includes an isolated nucleic acid that encodes a MOLX polypeptide, or a fragment, homolog, analog or derivative thereof. For example, the nucleic acid can encode a polypeptide at least 80% identical to a polypeptide comprising the amino acid sequences of SEQ ID NOS:2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 102, 104, 106, 108, 1 1 1 , 114, 1 16, 1 18, 120, 123, 125, 136, 138, 140, 142, 144, 146, 148, 150, 152, 154, 156, 158, 160, 162, 164, and 167. The nucleic acid can be, for example, a genomic DNA fragment or a cDNA molecule that includes the nucleic acid sequence of any of SEQ ID NOS:l, 3, 5, 7, 9, 1 1, 13, 15, 17, 19, 21, 23, 101, 103, 105, 107, 109, 112, 1 15, 117, 1 19, 121, 124, 135, 137, 139, 141, 143, 145, 147, 149, 151, 153, 155, 157, 159, 161, 163, 165, and 166.

Also included in the invention is an oligonucleotide, e.g., an oligonucleotide which includes at least 6 contiguous nucleotides of a MOLX nucleic acid (e.g., SEQ ID NOS:l, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 101, 103, 105, 107, 109, 112, 115, 117, 119, 121, 124, 135, 137, 139, 141, 143, 145, 147, 149, 151, 153, 155, 157, 159, 161, 163, 165, and 166) or a complement of said oligonucleotide.

Also included in the invention are substantially purified MOLX polypeptides (SEQ ID NOS:2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 102, 104, 106, 108, 11 1, 1 14, 1 16, 1 18, 120, 123, 125, 136, 138, 140, 142, 144, 146, 148, 150, 152, 154, 156, 158, 160, 162, 164, and 167). In certain embodiments, the MOLX polypeptides include an amino acid sequence that is substantially identical to the amino acid sequence of a human MOLX polypeptide. The invention also features antibodies that immunoselectively bind to MOLX polypeptides, or fragments, homologs, analogs or derivatives thereof.

In another aspect, the invention includes pharmaceutical compositions that include therapeutically- or prophylactically-effective amounts of a therapeutic and a pharmaceutically-acceptable carrier. The therapeutic can be, e.g., a MOLX nucleic acid, a MOLX polypeptide, or an antibody specific for a MOLX polypeptide. In a further aspect, the invention includes, in one or more containers, a therapeutically- or prophylactically- effective amount of this pharmaceutical composition.

In a further aspect, the invention includes a method of producing a polypeptide by culturing a cell that includes a MOLX nucleic acid, under conditions allowing for expression ofthe MOLX polypeptide encoded by the DNA. If desired, the MOLX polypeptide can then be recovered.

In another aspect, the invention includes a method of detecting the presence of a MOLX polypeptide in a sample. In the method, a sample is contacted with a compound that selectively binds to the polypeptide under conditions allowing for formation of a complex between the polypeptide and the compound. The complex is detected, if present, thereby identifying the MOLX polypeptide within the sample.

The invention also includes methods to identify specific cell or tissue types based on their expression of a MOLX. Also included in the invention is a method of detecting the presence of a MOLX nucleic acid molecule in a sample by contacting the sample with a MOLX nucleic acid probe or primer, and detecting whether the nucleic acid probe or primer bound to a MOLX nucleic acid molecule in the sample. In a further aspect, the invention provides a method for modulating the activity of a

MOLX polypeptide by contacting a cell sample that includes the MOLX polypeptide with a compound that binds to the MOLX polypeptide in an amount sufficient to modulate the activity of said polypeptide. The compound can be, e.g., a small molecule, such as a nucleic acid, peptide, polypeptide, peptidomimetic, carbohydrate, lipid or other organic (carbon-containing) or inorganic molecule, as further described herein.

Also within the scope ofthe invention is the use of a therapeutic in the manufacture of a medicament for treating or preventing disorders or syndromes including, e.g., endometriosis, fertility disorders, hypercoagulation, idiopathic thrombocytopenic purpura, immunodeficiencies, systemic lupus erythematosus, asthma, emphysema, scleroderma, allergy, ARDS, Von Hippel-Lindau (VHL) syndrome, Alzheimer's disease, stroke, tuberous sclerosis, hypercalceimia, Parkinson's disease, Huntington's disease, cerebral palsy, epilepsy, multiple sclerosis, ulcers, ataxia-telangiectasia, leukodystrophies, behavioral disorders, addiction, anxiety, pain, neuroprotection, osteoporosis, arthritis, ankylosing spondylitis, scoliosis, diabetes, autoimmune disease, myasthenia gravis, muscular dystrophy, renal artery stenosis, interstitial nephritis, glomerulonephritis, polycystic kidney disease, systemic lupus erythematosus, renal tubular acidosis, IgA nephropathy, Lesch-Nyhan syndrome, developmental disorders, growth disorders, and/or wounds, cardiomyopathy, atherosclerosis, hypertension, congenital heart defects, aortic stenosis, atrial septal defect (ASD), atrioventricular (A-V) canal defect, ductus arteriosus , pulmonary stenosis , subaortic stenosis, ventricular septal defect (VSD), valve diseases, obesity, transplantation, hemophilia, hypercoagulation, idiopathic thrombocytopenic purpura, immunodeficiencies, graft versus host disease (GVHD), lymphaedema, adrenoleukodystrophy, congenital adrenal hyperplasia, neuronal developmental, organizational, mediated and interactive disorders and disease; endocrine dysfunctions, growth and reproductive disorders, injury repair, cancer including but not limited to lung or breast cancer, endocrine disorders, inflammatory disorders, gastro-intestinal disorders and disorders of he respiratory system, Rheumatoid arthritis (RA), CNS disorders, Down syndrome, Schizophrenia, nutritional deficiencies, primary open-angle glaucoma (POAG), and bone disorders, hematopoietic disorders, or other disorders. The therapeutic can be, e.g., a MOLX nucleic acid, a MOLX polypeptide, or a MOLX-specific antibody, or biologically-active derivatives or fragments thereof.

For example, the compositions ofthe present invention will have efficacy for treatment of patients suffering from: Cancer including endometriosis, fertility disorders, hypercoagulation, idiopathic thrombocytopenic purpura, immunodeficiencies, systemic lupus erythematosus, asthma, emphysema, scleroderma, allergy, ARDS, Von Hippel- Lindau (VHL) syndrome, Alzheimer's disease, stroke, tuberous sclerosis, hypercalceimia, Parkinson's disease, Huntington's disease, cerebral palsy, epilepsy, multiple sclerosis, ulcers, ataxia-telangiectasia, leukodystrophies, behavioral disorders, addiction, anxiety, pain, neuroprotection, osteoporosis, arthritis, ankylosing spondylitis, scoliosis, diabetes, autoimmune disease, myasthenia gravis, muscular dystrophy, renal artery stenosis, interstitial nephritis, glomerulonephritis, polycystic kidney disease, systemic lupus erythematosus, renal tubular acidosis, IgA nephropathy, Lesch-Nyhan syndrome, developmental disorders, growth disorders, and/or wounds, cardiomyopathy, atherosclerosis, hypertension, congenital heart defects, aortic stenosis, atrial septal defect (ASD), atrioventricular (A-V) canal defect, ductus arteriosus , pulmonary stenosis , subaortic stenosis, ventricular septal defect (VSD), valve diseases, obesity, transplantation, hemophilia, hypercoagulation, idiopathic thrombocytopenic purpura, immunodeficiencies, graft versus host disease (GVHD), lymphaedema, adrenoleukodystrophy, congenital adrenal hyperplasia, neuronal developmental, organizational, mediated and interactive disorders and disease; endocrine dysfunctions, growth and reproductive disorders, injury repair, cancer including but not limited to lung or breast cancer, endocrine disorders, inflammatory disorders, gastro-intestinal disorders and disorders ofthe respiratory system, Rheumatoid arthritis (RA), CNS disorders, Down syndrome, Schizophrenia, nutritional deficiencies, primary open-angle glaucoma (POAG), and bone disorders, hematopoietic disorders and/or other pathologies and disorders ofthe like.

The polypeptides can be used as immunogens to produce antibodies specific for the invention and as vaccines. They can also be used to screen for potential agonist and antagonist compounds. For example, a cDNA encoding MOLX may be useful in gene therapy, and MOLX may be useful when administered to a subject in need thereof. By way of nonlimiting example, the compositions ofthe present invention will have efficacy for treatment of patients suffering from endometriosis, fertility disorders, hypercoagulation, idiopathic thrombocytopenic purpura, immunodeficiencies, systemic lupus erythematosus, asthma, emphysema, scleroderma, allergy, ARDS, Von Hippel- Lindau (VHL) syndrome, Alzheimer's disease, stroke, tuberous sclerosis, hypercalceimia, Parkinson's disease, Huntington's disease, cerebral palsy, epilepsy, multiple sclerosis, ulcers, ataxia-telangiectasia, leukodystrophies, behavioral disorders, addiction, anxiety, pain, neuroprotection, osteoporosis, arthritis, ankylosing spondylitis, scoliosis, diabetes, autoimmune disease, myasthenia gravis, muscular dystrophy, renal artery stenosis, interstitial nephritis, glomerulonephritis, polycystic kidney disease, systemic lupus erythematosus, renal tubular acidosis, IgA nephropathy, Lesch-Nyhan syndrome, developmental disorders, growth disorders, and/or wounds, cardiomyopathy, atherosclerosis, hypertension, congenital heart defects, aortic stenosis, atrial septal defect (ASD), atrioventricular (A-V) canal defect, ductus arteriosus , pulmonary stenosis , subaortic stenosis, ventricular septal defect (VSD), valve diseases, obesity, transplantation, hemophilia, hypercoagulation, idiopathic thrombocytopenic purpura, immunodeficiencies, graft versus host disease (GVHD), lymphaedema, adrenoleukodystrophy, congenital adrenal hyperplasia, neuronal developmental, organizational, mediated and interactive disorders and disease; endocrine dysfunctions, growth and reproductive disorders, injury repair, cancer including but not limited to lung or breast cancer, endocrine disorders, inflammatory disorders, gastro-intestinal disorders and disorders ofthe respiratory system, Rheumatoid arthritis (RA), CNS disorders, Down syndrome, Schizophrenia, nutritional deficiencies, primary open-angle glaucoma (POAG), and bone disorders, hematopoietic disorders and/or other pathologies and disorders.

The invention further includes a method for screening for a modulator of disorders or syndromes including, e.g., endometriosis, fertility disorders, hypercoagulation, idiopathic thrombocytopenic purpura, immunodeficiencies, systemic lupus erythematosus, asthma, emphysema, scleroderma, allergy, ARDS, Von Hippel-Lindau (VHL) syndrome, Alzheimer's disease, stroke, tuberous sclerosis, hypercalceimia,

Parkinson's disease, Huntington's disease, cerebral palsy, epilepsy, multiple sclerosis, ulcers, ataxia-telangiectasia, leukodystrophies, behavioral disorders, addiction, anxiety, pain, neuroprotection, osteoporosis, arthritis, ankylosing spondylitis, scoliosis, diabetes, autoimmune disease, myasthenia gravis, muscular dystrophy, renal artery stenosis, interstitial nephritis, glomerulonephritis, polycystic kidney disease, systemic lupus erythematosus, renal tubular acidosis, IgA nephropathy, Lesch-Nyhan syndrome, developmental disorders, growth disorders, and/or wounds, cardiomyopathy, atherosclerosis, hypertension, congenital heart defects, aortic stenosis, atrial septal defect

(ASD), atrioventricular (A-V) canal defect, ductus arteriosus , pulmonary stenosis , subaortic stenosis, ventricular septal defect (VSD), valve diseases, obesity, transplantation, hemophilia, hypercoagulation, idiopathic thrombocytopenic purpura, immunodeficiencies, graft versus host disease (GVHD), lymphaedema, adrenoleukodystrophy, congenital adrenal hyperplasia, neuronal developmental, organizational, mediated and interactive disorders and disease; endocrine dysfunctions, growth and reproductive disorders, injury repair, cancer including but not limited to lung or breast cancer, endocrine disorders, inflammatory disorders, gastro-intestinal disorders and disorders ofthe respiratory system, Rheumatoid arthritis (RA), CNS disorders, Down syndrome, Schizophrenia, nutritional deficiencies, primary open-angle glaucoma (POAG), and bone disorders, hematopoietic disorders or other disorders related to cell signal processing and metabolic pathway modulation. The method includes contacting a test compound with a MOLX polypeptide and determining if the test compound binds to said MOLX polypeptide. Binding ofthe test compound to the MOLX polypeptide indicates the test compound is a modulator of activity, or of latency or predisposition to the aforementioned disorders or syndromes.

Also within the scope ofthe invention is a method for screening for a modulator of activity, or of latency or predisposition to an disorders or syndromes including, e.g., endometriosis, fertility disorders, hypercoagulation, idiopathic thrombocytopenic purpura, immunodeficiencies, systemic lupus erythematosus, asthma, emphysema, scleroderma, allergy, ARDS, Von Hippel-Lindau (VHL) syndrome, Alzheimer's disease, stroke, tuberous sclerosis, hypercalceimia, Parkinson's disease, Huntington's disease, cerebral palsy, epilepsy, multiple sclerosis, ulcers, ataxia-telangiectasia, leukodystrophies, behavioral disorders, addiction, anxiety, pain, neuroprotection, osteoporosis, arthritis, ankylosing spondylitis, scoliosis, diabetes, autoimmune disease, myasthenia gravis, muscular dystrophy, renal artery stenosis, interstitial nephritis, glomerulonephritis, polycystic kidney disease, systemic lupus erythematosus, renal tubular acidosis, IgA nephropathy, Lesch-Nyhan syndrome, developmental disorders, growth disorders, and/or wounds, cardiomyopathy, atherosclerosis, hypertension, congenital heart defects, aortic stenosis, atrial septa! defect (ASD), atrioventricular (A-V) canal defect, ductus arteriosus , pulmonary stenosis , subaortic stenosis, ventricular septal defect (VSD), valve diseases, obesity, transplantation, hemophilia, hypercoagulation, idiopathic thrombocytopenic purpura, immunodeficiencies, graft versus host disease (GVHD), lymphaedema, adrenoleukodystrophy, congenital adrenal hyperplasia, neuronal developmental, organizational, mediated and interactive disorders and disease; endocrine dysfunctions, growth and reproductive disorders, injury repair, cancer including but not limited to lung or breast cancer, endocrine disorders, inflammatory disorders, gastro-intestinal disorders and disorders ofthe respiratory system, Rheumatoid arthritis (RA), CNS disorders, Down syndrome, Schizophrenia, nutritional deficiencies, primary open-angle glaucoma (POAG), and bone disorders, hematopoietic disorders or other disorders related to cell signal processing and metabolic pathway modulation by administering a test compound to a test animal at increased risk for the aforementioned disorders or syndromes. The test animal expresses a recombinant polypeptide encoded by a MOLX nucleic acid. Expression or activity of MOLX polypeptide is then measured in the test animal, as is expression or activity ofthe protein in a control animal which recombinantly-expresses MOLX polypeptide and is not at increased risk for the disorder or syndrome. Next, the expression of MOLX polypeptide in both the test animal and the control animal is compared. A change in the activity of MOLX polypeptide in the test animal relative to the control animal indicates the test compound is a modulator of latency ofthe disorder or syndrome. In yet another aspect, the invention includes a method for determining the presence of or predisposition to a disease associated with altered levels of a MOLX polypeptide, a MOLX nucleic acid, or both, in a subject (e.g., a human subject). The method includes measuring the amount ofthe MOLX polypeptide in a test sample from the subject and comparing the amount ofthe polypeptide in the test sample to the amount ofthe MOLX polypeptide present in a control sample. An alteration in the level ofthe MOLX polypeptide in the test sample as compared to the control sample indicates the presence of or predisposition to a disease in the subject. Preferably, the predisposition includes, e.g., endometriosis, fertility disorders, hypercoagulation, idiopathic thrombocytopenic purpura, immunodeficiencies, systemic lupus erythematosus, asthma, emphysema, scleroderma, allergy, ARDS, Von Hippel-Lindau (VHL) syndrome, Alzheimer's disease, stroke, tuberous sclerosis, hypercalceimia, Parkinson's disease, Huntington's disease, cerebral palsy, epilepsy, multiple sclerosis, ulcers, ataxia-telangiectasia, leukodystrophies, behavioral disorders, addiction, anxiety, pain, neuroprotection, osteoporosis, arthritis, ankylosing spondylitis, scoliosis, diabetes, autoimmune disease, myasthenia gravis, muscular dystrophy, renal artery stenosis, interstitial nephritis, glomerulonephritis, polycystic kidney disease, systemic lupus erythematosus, renal tubular acidosis, IgA nephropathy, Lesch-Nyhan syndrome, developmental disorders, growth disorders, and/or wounds, cardiomyopathy, atherosclerosis, hypertension, congenital heart defects, aortic stenosis, atrial septal defect (ASD), atrioventricular (A-V) canal defect, ductus arteriosus , pulmonary stenosis , subaortic stenosis, ventricular septal defect (VSD), valve diseases, obesity, transplantation, hemophilia, hypercoagulation, idiopathic thrombocytopenic purpura, immunodeficiencies, graft versus host disease (GVHD), lymphaedema, adrenoleukodystrophy, congenital adrenal hyperplasia, neuronal developmental, organizational, mediated and interactive disorders and disease; endocrine dysfunctions, growth and reproductive disorders, injury repair, cancer including but not limited to lung or breast cancer, endocrine disorders, inflammatory disorders, gastro-intestinal disorders and disorders ofthe respiratory system, Rheumatoid arthritis (RA), CNS disorders, Down syndrome, Schizophrenia, nutritional deficiencies, primary open-angle glaucoma (POAG), and bone disorders, hematopoietic disorders. Also, the expression levels ofthe new polypeptides ofthe invention can be used in a method to screen for various cancers as well as to determine the stage of cancers.

In a further aspect, the invention includes a method of treating or preventing a pathological condition associated with a disorder in a mammal by administering to the subject a MOLX polypeptide, a MOLX nucleic acid, or a MOLX-specific antibody to a subject (e.g., a human subject), in an amount sufficient to alleviate or prevent the pathological condition. In preferred embodiments, the disorder, includes, e.g., endometriosis, fertility disorders, hypercoagulation, idiopathic thrombocytopenic purpura, immunodeficiencies, systemic lupus erythematosus, asthma, emphysema, scleroderma, allergy, ARDS, Von Hippel-Lindau (VHL) syndrome, Alzheimer's disease, stroke, tuberous sclerosis, hypercalceimia, Parkinson's disease, Huntington's disease, cerebral palsy, epilepsy, multiple sclerosis, ulcers, ataxia-telangiectasia, leukodystrophies, behavioral disorders, addiction, anxiety, pain, neuroprotection, osteoporosis, arthritis, ankylosing spondylitis, scoliosis, diabetes, autoimmune disease, myasthenia gravis, muscular dystrophy, renal artery stenosis, interstitial nephritis, glomerulonephritis, polycystic kidney disease, systemic lupus erythematosus, renal tubular acidosis, IgA nephropathy, Lesch-Nyhan syndrome, developmental disorders, growth disorders, and/or wounds, cardiomyopathy, atherosclerosis, hypertension, congenital heart defects, aortic stenosis, atrial septal defect (ASD), atrioventricular (A-V) canal defect, ductus arteriosus , pulmonary stenosis , subaortic stenosis, ventricular septal defect (VSD), valve diseases, obesity, transplantation, hemophilia, hypercoagulation, idiopathic thrombocytopenic purpura, immunodeficiencies, graft versus host disease (GVHD), lymphaedema, adrenoleukodystrophy, congenital adrenal hyperplasia, neuronal developmental, organizational, mediated and interactive disorders and disease; endocrine dysfunctions, growth and reproductive disorders, injury repair, cancer including but not limited to lung or breast cancer, endocrine disorders, inflammatory disorders, gastro-intestinal disorders and disorders ofthe respiratory system, Rheumatoid arthritis (RA), CNS disorders, Down syndrome, Schizophrenia, nutritional deficiencies, primary open-angle glaucoma (POAG), and bone disorders, hematopoietic disorders, and/or other diseases or disorders.

In yet another aspect, the invention can be used in a method to identity the cellular receptors and downstream effectors ofthe invention by any one of a number of techniques commonly employed in the art. These include but are not limited to the two-hybrid system, affinity purification, co-precipitation with antibodies or other specific-interacting molecules.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing ofthe present invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In the case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting. Other features and advantages ofthe invention will be apparent from the following detailed description and claims.

DETAILED DESCRIPTION OF THE INVENTION

The invention is based, in part, upon the discovery of novel nucleic acid sequences that encode novel polypeptides. The novel nucleic acids and their encoded polypeptides are referred to individually as MOL1-MOL23. The nucleic acids, and their encoded polypeptides, are collectively designated herein as "MOLX".

The novel MOLX nucleic acids ofthe invention include the nucleic acids whose sequences are provided in the tables herein, or a fragment, derivative, analog or homolog thereof. The novel MOLX proteins ofthe invention include the protein fragments whose sequences are provided in the tables herein The individual MOLX nucleic acids and proteins are described below. Within the scope of this invention is a method of using these nucleic acids and peptides in the treatment or prevention of a disorder related to cell signaling or metabolic pathway modulation.

MOL1

MOLla

A disclosed Notch-like nucleic acid of 7410 nucleotides, MOLla, alternatively referred to as SC29674552_EXT, is shown in Table 1 A. The disclosed MOLla open reading frame ("ORF") begins at the ATG initiation codon at nucleotides 1-3 and terminates at a TGA codon at nucleotides 7408-7410. In Table 1A, the start and stop codons are depicted with bold letters.

Table 1A. MOLla nucleotide sequence (SEQ ID NO:l).

ATGCCCGCCCTGCGCCCCGCTCTGCTGTGGGCGCTGCTGGCGCXCTGGCTGTGCTGCGCGACCCCCGCGCATGCATT GCAGTGTCGAGATGGCTATGAACCCTGTGTAAATGAAGGAATGTGTGTTACCTACCACAATGGCACAGGATACTGCA AATGTCCAGAAGGCTTCTTGGGGGAATATTGTCAACATCGAGACCCCTGTGAGAAGAACCGCTGCCAGAATGGTGGG ACTTGTGTGGCCCAGGCCATGCTGGGGAAAGCCACGTGCCGATGTGCCTCAGGGTTTACAGGAGAGGACTGCCAGTA CTCGACATCTCATCCATGCTTTGTGTCTCGACCTTGCCTGAATGGCGGCACATGCCATATGCTCAGCCGGGATACCT ATGAGTGCACCTGTCAAGTCGGGTTTACAGGTAAGGAGTGCCAATGGACGGATGCCTGCCTGTCTCATCCCTGTGCA AATGGAAGTACCTGTACCACTGTGGCCAACCAGTTCTCCTGCAAATGCCTCACAGGCTTCACAGGGCAGAAATGTGA GACTGATGTCAATGAGTGTGACATTCCAGGACACTGCCAGCATGGTGGCACCTGCCTCAACCTGCCTGGTTCCTACC AGTGCCAGTGCCCTCAGGGCTTCACAGGCCAGTACTGTGACAGCCTGTATGTGCCCTGTGCACCCTCACCTTGTGTC AATGGAGGCACCTGTCGGCAGACTGGTGACTTCACTTTTGAGTGCCATTTACCAGGTTTTGAAGGGAGCACCTGTGA GAGGAATATTGATGACTGCCCTAACCACAGGTGTCAGAATGGAGGGGTTTGTGTGGATGGGGTCAACACTTACAACT GCCGCTGTCCCCCACAATGGACAGGACAGTTCTGCACAGAGGATGTGGATGAATGCCTGCTGCAGCCCAATGCCTGT CAAAACTGGGGCACCTGTGCCAACCGCAATGGAGGCTATGGCTGTGTATGTGTCAACGGCTGGAGTGGAGATGACTG CAGTGAGAACATTGATGATTGTGCTTTCGGCGCCTGTACTCCAGGCTCCACCTGCATCGACCGTGTGGCCTCCTTCT CTTGCATGTGCCCAGAGGGGAAGGCAGGTCTCCTGTGTCATCTGGATGATGCATGCATCAGCAATCCTTGCCACAAG GGGGCACTGTGTGACACCAACCCCCTAAATGGGCAATATATTTGCACCTGCCCACAAGGCTACAAAGGGGCTGACTG CACAGAAGATGTGGATGAATGTGCCATGGCCAATAGCAATCCTTGTGAGCATGCAGGAAAATGTGTGAACACGGATG GCGCCTTCCACTGTGAGTGTCTGAAGGGTTATGCAGGACCTCGTTGTGAGATGGACATCAATGAGTGCCATTCAGAC CCCTGCCAGAATGATGCTACCTGTCTGGATAAGATTGGAGGCTTCACATGTCTGTGCATGCCAGGTTTCAAAGGTGT GCATTGTGAATTAGAAATAAATGAATGTCAGAGCAACCCTTGTGTGAACAATGGGCAGTGTGTGGATAAAGTCAATC GTTTCCAGTGCCTGTGTCCTCCTGGTTTCACTGGGCCAGTTTGCCAGATTGATATTGATGACTGTTCCAGTACTCCG TGTCTGAATGGGGCAAAGTGTATCGATCACCCGAATGGCTATGAATGCCAGTGTGCCACAGGTTTCACTGGTGTGTT GTGTGAGGAGAACATTGACAACTGTGACCCCGATCCTTGCCACCATGGTCAGTGTCAGGATGGTATTGATTCCTACA CCTGCATCTGCAATCCCGGGTACATGGGCGCCATCTGCAGTGACCAGATTGATGAATGTTACAGCAGCCCTTGCCTG AACGATGGTCGCTGCATTGACCTGGTCAATGGCTACCAGTGCAACTGCCAGCCAGGCACGTCAGGTGTTAATTGTGA AATTAATTTTGATGACTGTGCAAGTAACCCTTGTATCCATGGAATCTGTATGGATGGCATTAATCGCTACAGTTGTG TCTGCTCACCAGGATTCACAGGGCAGAGATGTAACATTGACATTGATGAGTGTGCCTCCAATCCCTGTCGCAAGGGT GCAACATGTATCAACGGTGTGAATGGTTTCCGCTGTATATGCCCCGAGGGACCCCATCACCCCAGCTGCTACTCACA GGTGAACGAATGCCTGAGCAATCCCTGCATCCATGGAAACTGTACTGGAGGTCTCAGTGGATATAAGTGTCTCTGTG ATGCAGGCTGGGTTGGCATCAACTGTGAAGTGGACAAAAATGAATGCCTTTCGAATCCATGCCAGAATGGAGGAACT TGTGACAATCTGGTGAATGGATACAGGTGTACTTGCAAGAAGGGCTTTAAAGGCTATAACTGCCAGGTGAATATTGA TGAATGTGCCTCAAATCCATGCCTGAACCAAGGAACCTGCTTTGATGACATAAGTGGCTACACTTGCCACTGTGTGC TGCCATACACAGGTAAGAATTGTCAGACAGTATTGGCTCCCTGTTCCCCAAACCCTTGTGAGAATGCTGCTGTTTGC AAAGAGTCACCAAATTTTGAGAGTTATACTTGCTTGTGTGCTCCTGGCTGGCAAGGTCAGCGGTGTACCATTGACAT TGACGAGTGTATCTCCAAGCCCTGCATGAACCATGGTCTCTGCCATAACACCCAGGGCAGCTACATGTGTGAATGTC CACCAGGCTTCAGTGGTATGGACTGTGAGGAGGACATTGATGACTGCCTTGCCAGTCCTTGCCAGAATGGAGGTTCC TGTATGGATGGAGTGAATACTTTCTCCTGCCTCTGCCTTCCGGGTTTCACTGGGGATAAGTGCCAGACAGACATGAA TGAGTGTCTGAGTGAACCCTGTAAGAATGGAGGGACCTGCTCTGACTACGTCAACAGTTACACTTGCAAGTGCCAGG CAGGATTTGATGGAGTCCATTGTGAGAACAACATCAATGAGTGCACTGAGAGCTCCTGTTTCAATGGTGGCACATGT GTTGATGGGATTAACTCCTTCTCTTGCTTGTGCCCTGTGGGTTTCACTGGATCCTTCTGCCTCCATGAGATCAATGA ATGCAGCTCTCATCCATGCCTGAATGATGGAACGTGTGTTGATGGCCTGGGTACCTACCGCTGCAGCTGCCCCCTGG GCTACACTGGGAAAAACTGTCAGACCCTGGTGAATCTCTGCAGTCGGTCTCCATGTAAAAACAAAGGTACTTGCGTT CAGAAAAAAGCAGAGTCCCAGTGCCTATGTCCATCTGGATGGGCTGGTGCCTATTGTGACGTGCCCAATGTCTCTTG TGACATAGCAGCCTCCAGGAGAGGTGTGCTTGTTGAACACTTGTGCCAGCACTCAGGTGTCTGCATCAATGCTGGCA ACACGCATTACTGTCAGTGCCCCCTGGGCTATACTGGGAGCTACTGTGAGGAGCAACTCGATGAGTGTGCGTCCAAC CCCTGCCAGCACGGGGCAACATGCAGTGACTTCATTGGTGGATACAGATGCGAGTGTGTCCCAGGCTATCAGGGTGT CAACTGTGAGTATGAAGTGGATGAGTGCCAGAATCAGCCCTGCCAGAATGGAGGCACCTGTATTGACCTTGTGAACC ATTTCAAGTGCTCTTGCCCACCAGGCACTCGGGGTATGAAATCATCCTTATCCATTTTCCATTGCCCGGGTCCCCAT TGCCTTAATGGTGGTCAGTGCATGGATAGGATTGGAGGCTACAGTTGTCGCTGCTTGCCTGGCTTTGCTGGGGAGCG TTGTGAGGGAGACATCAACGAGTGCCTCTCCAACCCCTGCAGCTCTGAGGGCAGCCTGGACTGTATACAGCTCACCA ATGACTACCTGTGTGTTTGCCGTAGTGCCTTTACTGGTCGGCACTGTGAAACCTTCGTCGATGTGTGTCCCCAGATG CCCTGCCTGAATGGAGGGACTTGTGCTGTGGCCAGTAACATGCCTGATGGTTCATTTGCCGTTGTCCCCCAGGGATT TTCCGGGGCAAGGTGCCAGAGCAGCTGTGGACAAGTGAAATGTAGGAAGGGGGAGCAGTGTGTGCACACCGCCTCTG GACCCCGCTGCTTCTGCCCCAGTCCCCGGGACTGCGAGTCAGGCTGTGCCAGTAGCCCCTGCCAGCACGGGGGCAGC TGCCACCCTCAGCGCCAGCCTCCTTATTACTCCTGCCAGTGTGCCCCACCATTCTCGGGTAGCCGCTGTGAACTCTA CACGGCACCCCCCAGCACCCCTCCTGCCACCTGTCTGAGCCAGTATTGTGCCGACAAAGCTCGGGATGGCGTCTGTG ATGAGGCCTGCAACAGCCATGCCTGCCAGTGGGATGGGGGTGACTGTTCTCTCACCATGGAGAACCCCTGGGCCAAC TGCTCCTCCCCACTTCCCTGCTGGGATTATATCAACAACCAGTGTGATGAGCTGTGCAACACGGTCGAGTGCCTGTT TGACAACTTTGAATGCCAGGGGAACAGCAAGACATGCAAGTATGACAAATACTGTGCAGACCACTTCAAAGACAACC ACTGTGACCAGGGGTGCAACAGTGAGGAGTGTGGTTGGGATGGGCTGGACTGTGCTGCTGACCAACCTGAGAACCTG GCAGAAGGTACCCTGGTTATTGTGGTATTGATGCCACCTGAACAACTGCTCCAGGATGCTCGCAGCTTCTTGCGGGC ACTGGGTACCCTGCTCCACACCAACCTGCGCATTAAGCGGGACTCCCAGGGGGAACTCATGGTGTACCCCTATTATG GTGAGAAGTCAGCTGCTATGAAGAAACAGAGGATGACACGCAGATCCCTTCCTGGTGAACAAGAACAGGAGGTGGCT GGGTCTAAAGTCTTTCTGGAAATTGACAACCGCCAGTGTGTTCAAGACTCAGACCACTGCTTCAAGAACACGGATGC AGCAGCAGCTCTCCTGGCCTCTCACGCCATACAGGGGACCCTGTCATACCCTCTTGTGTCTGTCGTCAGTGAGTCCC TGACTCCAGAACGCACTCAGCTCCTCTATCTCCTTGCTGTTGCTGTTGTCATCATTCTGTTTATTATTCTGCTGGGG GTAATCATGGCAAAACGAAAGCGTAAGCATGGCTCTCTCTGGCTGCCTGAAGGTTTCACTCTTCGCCGAGATGCAAG CAATCACAAGCGTCGTGAGCCAGTGGGACAGGATGCTGTGGGGCTGAAAAATCTCTCAGTGCAAGTCTCAGAAGCTA ACCTAATTGGTACTGGAACAAGTGAACACTGGGTCGATGATGAAGGGCCCCAGCCAAAGAAAGTAAAGGCTGAAGAT GAGGCCTTACTCTCAGAAGAAGATGACCCCATTGATCGACGGCCATGGACACAGCAGCACCTTGAAGCTGCAGACAT CCGTAGGACACCATCGCTGGCTCTCACCCCTCCTCAGGCAGAGCAGGAGGTGGATGTGTTAGATGTGAATGTCCGTG GCCCAGATGGCTGCACCCCATTGATGTTGGCTTCTCTCCGAGGAGGCAGCTCAGATTTGAGTGATGAAGATGAAGAT GCAGAGGACTCTTCTGCTAACATCATCACAGACTTGGTCTACCAGGGTGCCAGCCTCCAGGCCCAGACAGACCGGAC TGGTGAGATGGCCCTGCACCTTGCAGCCCGCTACTCACGGGCTGATGCTGCCAAGCGTCTCCTGGATGCAGGTGCAG ATGCCAATGCCCAGGACAACATGGGCCGCTGTCCACTCCATGCTGCAGTGGCAGCTGATGCCCAAGGTGTCTTCCAG ATTCTGATTCGCAACCGAGTAACTGATCTAGATGCCAGGATGAATGATGGTACTACACCCCTGATCCTGGCTGCCCG CCTGGCTGTGGAGGGAATGGTGGCAGAACTGATCAACTGCCAAGCGGATGTGAATGCAGTGGATGACCATGGAAAAT CTGCTCTTCACTGGGCAGCTGCTGTCAATAATGTGGAGGCAACTCTTTTGTTGTTGAAAAATGGGGCCAACCGAGAC ATGCAGGACAACAAGGAAGAGACACCTCTGTTTCTTGCTGCCCGGGAGGGGAGCTATGAAGCAGCCAAGATCCTGTT AGACCATTTTGCCAATCGAGACATCACAGACCATATGGATCGTCTTCCCCGGGATGTGGCTCGGGATCGCATGCACC ATGACATTGTGCGCCTTCTGGATGAATACAATGTGACCCCAAGCCCTCCAGGCACCGTGTTGACTTCTGCTCTCTCA CCTGTCATCTGTGGGCCCAACAGATCTTTCCTCAGCCTGAAGCACACCCCAATGGGCAAGAAGTCTAGACGGCCCAG TGCCAAGAGTACCATGCCTACTAGCCTCCCTAACCTTGCCAAGGAGGCAAAGGATGCCAAGGGTAGTAGGAGGAAGA AGTCTCTGAGTGAGAAGGTCCAACTGTCTGAGAGTTCAGTAACTTTATCCCCTGTTGATTCCCTAGAATCTCCTCAC ACGTATGTTTCCGACACCACATCCTCTCCAATGATTACATCCCCTGGGATCTTACAGGCCTCACCCAACCCTATGTT GGCCACTGCCGCCCCTCCTGCCCCAGTCCATGCCCAGCATGCACTATCTTTTTCTAACCTTCATGAAATGCAGCCTT TGGCACATGGGGCCAGCACTGTGCTTCCCTCAGTGAGCCAGTTGCTATCCCACCACCACATTGTGTCTCCAGGCAGT GGCAGTGCTGGAAGCTTGAGTAGGCTCCATCCAGTCCCAGTCCCAGCAGATTGGATGAACCGCATGGAGGTGAATGA GACCCAGTACAATGAGATGTTTGGTATGGTCCTGGCTCCAGCTGTAGGGCACCCATCCTGGCATAGCTCCCCAGAGA GGCCACCTGAAGGGAAGCACATAACCACCCCTCGGGAGCCCTTGCCCCCCATTGTGACTTTCCAGCTCATCCCTAAA GGCAGTATTGCCCAACCAGCGGGGGCTCCCCAGCCTCAGTCCACGTGCCCTCCAGCTGTTGCGGGCCCCCTGCCCAC CATGTACCAGATTCCAGAAATGGCCCGTTTGCCCAGTGTGGCTTTCCCCACTGCCATGATGCCCCAGCAGGACGGGC AGGTAGCTCAGACCATTCTCCCAGCCTATCATCCTTTCCCAGCCTCTGTGGGCAAGTACCCCACACCCCCTTCACAG CACAGTTATGCTTCCTCAAATGCTGCTGAGCGAACACCCAGTCACAGTGGTCACCTCCAGGGTGAGCATCCCTACCT GACACCATCCCCAGAGTCTCCTGACCAGTGGTCAAGTTCATCACCCCACTCTGCTTCTGACTGGTCAGATGTGACCA CCAGCCCTACCCCTGGGGGAGCTGGAGGAGGTCAGCGGGGACCTGGGACACACATGTCTGAGCCACCACACAACAAC ATGCAGGTTTATGCGTGA

The disclosed MOLla nucleotide encodes a protein which has 2469 amino acid residues, referred to as the MOLla protein. The MOLla protein was analyzed for signal peptide prediction and cellular localization. SignalP results predict that MOLla is cleaved between position 25 and 26 (AHA-LQ) of SEQ ID NO:2. Psort and Hydropathy profiles also predict that MOLla contains a signal peptide and is likely to be localized in the plasma membrane (Certainty=0.4600). A disclosed MOLla polypeptide sequence is presented in Table IB using the one-letter amino acid code.

Table IB. Encoded MOLla protein sequence (SEQ ID NO:2).

MPALRPALL ALLAL CCATPAHALQCRDGYEPCVNEGMCVTyHNGTGYCKCPEGF GEYCQHRDPCEKNRCQNGG TCVAQA LGKATCRCASGFTGEDCQYSTSHPCFVSRPCLNGGTCHMLSRDTYECTCQVGFTGKECQ TDACLSHPCA NGSTCTTVANQFSCKCLTGFTGQKCETDVNECDIPGHCQHGGTC N PGSYQCQCPQGFTGQYCDSLYVPCAPSPCV NGGTCRQTGDFTFECHLPGFEGSTCERNIDDCPNHRCQNGGVCVDGλ/NTYNCRCPPQ TGQFCTEDVDECLLQPNAC QNWGTCANRNGGYGCVCVNGWSGDDCSENIDDCAFGACTPGSTCIDRVASFSCMCPEGKAG LCHLDDACISNPCHK GALCDTNP NGQYICTCPQGYKGADCTEDVDECAMANSNPCEHAGKCVNTDGAFHCEC KGYAGPRCEMDINECHSD PCQNDATCLDKIGGFTCLCMPGF GVHCE EINECQSNPCVNNGQCVDKVNRFQCLCPPGFTGPVCQIDIDDCSSTP CLNGAKCIDHPNGYECQCATGFTGVLCEENIDNCDPDPCHHGQCQDGIDSYTCICNPGYMGAICSDQIDECYSSPCL NDGRCIDLWGYQCNCQPGTSGVNCEINFDDCASNPCIHGICMDGINRYSCVCSPGFTGQRCNIDIDECASNPCRKG ATCINGVNGFRCICPEGPHHPSCYSQV ECLSNPCIHGNCTGGLSGYKC CDAGWVGINCEVDKNECLSNPCQNGGT CDNLVNGYRCTCKKGFKGYNCQVNIDECASNPC NQGTCFDDISGYTCHCV PYTGKNCQTVLAPCSPNPCENAAVC KESPNFESYTCLCAPGWQGQRCTIDIDECISKPCMNHG CH TQGSYMCECPPGFSGMDCEEDIDDCLASPCQNGGS CMDGVNTFSCLCLPGFTGDKCQTDMNECLSEPCKNGGTCSDYVNSYTCKCQAGFDGVHCEN INECTESSCFNGGTC VDGINSFSCLCPVGFTGSFCLHEINECSSHPC NDGTCVDGLGTYRCSCPLGYTGKNCQTLVN CSRSPCKNKGTCV QKKAESQC CPSGWAGAYCDVPNVSCDIAASRRGV VEH CQHSGVCINAGNTHYCQCPLGYTGSYCEEQLDECASN PCQHGATCSDFIGGYRCECVPGYQGVNCEYEVDECQNQPCQNGGTCID VNHFKCSCPPGTRGMKSS SIFHCPGPH CLNGGQCMDRIGGYSCRCLPGFAGERCEGDINEC SWPCSSEGSLDCIQ TNDYLCVCRSAFTGRHCETFVDVCPQM PCLNGGTCAVASNMPDGSFAWPQGFSGARCQSSCGQVKCRKGEQCVHTASGPRCFCPSPRDCESGCASSPCQHGGS CHPQRQPPYYSCQCAPPFSGSRCELYTAPPSTPPATCLSQYCADKARDGVCDEACNSHACQ DGGDCSLTMENPWAN CSSPLPC DYINNQCDE CNTVECLFDNFECQGNS TCKYDKYCADHFKDNHCDQGCNSEECG DG DCAADQPENL AEGTLVIWLMPPEQLLQDARSF RA GT HTN RIKRDSQGELMVYPYYGEKSAAMKKQRMTRRSLPGEQEQEVA GSKVFLEIDNRQCVQDSDHCFKNTDAAAAL ASHAIQGT SYPLVSWSESLTPERTQLLYLLAVAWIILFIIL G VIMAKRKR HGSLWLPEGFT RRDASNHKRREPVGQDAVGLKNLSVQVSEANLIGTGTSEHWVDDEGPQPKKVKAED EALLSEEDDPIDRRP TQQHLEAADIRRTPSLALTPPQAEQEVDV DVNVRGPDGCTPLMLASLRGGSSDLSDEDED AEDSSA IITD VYQGASLQAQTDRTGEMALHLAARYSRADAAKRLLDAGADANAQDNMGRCPIJHAAVAADAQGVFQ ILIR RVTD DARMNDGTTPLILAARLAVEGMVAELINCQADV AVDDHGKSALH AAAλ7NNVEATLLLLKNGANRD MQDN EETP FLAAREGSYEAA I DHFA RDITDHMDRLPRDVARDRMHHDIVRLLDEYNVTPSPPGTV TSALS PVICGPNRSFLSLKHTP GKKSRRPSAKSTMPTS PNLAKEAKDAKGSRRKKSLSEKVQLSESSVTLSPVDS ESPH TYVSDTTSSPMITSPGILQASPNPM ATAAPPAPVHAQHALSFSNLHEMQPLAHGASTVLPSVSQ SHHHIVSPGS GSAGS SRLHPVPVPAD MNRMEVNETQY EMFGMV APAVGHPSWHSSPERPPEGKHITTPREPLPPIVTFQ IPK GSIAQPAGAPQPQSTCPPAVAGPLPTMYQIPEMARLPSVAFPTAMMPQQDGQVAQTILPAYHPFPASVGKYPTPP5Q HSYAΞSNAAERTPSHSGH QGEHPY TPSPESPDQ SSSSPHSASD SDVTTSPTPGGAGGGQRGPGTHMSEPPHNN MQVYA

A region ofthe MOLla nucleic acid sequence has 6436 of 7416 bases (86%) identical to a Rattits norvegictis Notch-like protein mRNA (GENBANK- ID:RATNOTCHX | acc:M93661), with an E-value of 0.0. In all BLAST alignments herein, the "E-value" or "Expect" value is a numeric indication ofthe probability that the aligned sequences could have achieved their similarity to the BLAST query sequence by chance alone, within the database that was searched. For example, the probability that the subject ("Sbjct") retrieved from the MOLla BLAST analysis, e.g., the Raltus norvegiciis Notch-like protein mRNA, matched the Query MOLla sequence purely by chance is 0.0. MOLla also has 2443 of 2471 amino acid residues (98%) positive with patp:AAY06816 . Human Notch2 (humN2) protein sequence - Homo sapiens, 2471 aa. The Expect value is used as a convenient way to create a significance threshold for reporting results. The default value used for blasting is typically set to 0.0001. In BLAST 2.0, the Expect value is also used instead ofthe P value (probability) to report the significance of matches. For example, an E value of one assigned to a hit can be interpreted as meaning that in a database ofthe current size one might expect to see one match with a similar score simply by chance. An E value of zero means that one would not expect to see any matches with a similar score simply by chance. See, e.g., http://www.ncbi.nlm.nih.gov/Education/BLASTinfo/. Occasionally, a string of X's or N's will result from a BLAST search. This is a result of automatic filtering ofthe query for low-complexity sequence that is performed to prevent artifactual hits. The filter substitutes any low-complexity sequence that it finds with the letter "N" in nucleotide sequence (e.g., "N NNNNNNNN NN'¹) or the letter "X" in protein sequences (e.g., "XXXXXXXXX"). Low-complexity regions can result in high scores that reflect compositional bias rather than significant position-by-position alignment. Wootton and Federhen, Methods Enzymol 266:554-571, 1996.

Utilities for the MOLX nucleic acids and their encoded polypeptides can be inferred based on the homology ofthe disclosed MOLX nucleic acids and/or polypeptides (including domains ofthe encoded polypeptides) to previously described sequences.

MOLla expression in different tissues was examined through TaqMan as described below in Example 1.

MOLla is expressed in at least the following tissues: kidney, brain, lymph node, muscle, hippocampus, bone marrow, placenta, thyroid, para-thyroid, prostate, testis, epidermis, ovary, coronary artery, liver, lung, spinal cord, stomach, breast, lung, uterus, and colon. It is likely that Notch proteins are expressed in all tissues, so the widespread expression of MOLla agrees with its homology with Notch.

One or more consensus positions (Cons. Pos.) ofthe nucleotide sequence of MOLla have been identified as single nucleotide polymorphisms (SNPs) as shown in Table IC. A dash ("-"), when shown, means that a base is not present. The sign ">" means "is changed to". SNPs were identified using the techniques disclosed in Example 3.

MOLlb

MOLla was subjected to the exon linking process to confirm the sequence. PCR primers were designed by starting at the most upstream sequence available, for the forward primer, and at the most downstream sequence available for the reverse primer. In each case, the sequence was examined, walking inward from the respective termini toward the coding sequence, until a suitable sequence that is either unique or highly selective was encountered, or, in the case ofthe reverse primer, until the stop codon was reached. Such primers were designed based on in silico predictions for the full length cDNA, part (one or more exons) ofthe DNA or protein sequence ofthe target sequence, or by translated homology ofthe predicted exons to closely related human sequences sequences from other species. These primers were then employed in PCR amplification based on the following pool of human cDNAs: adrenal gland, bone marrow, brain - amygdala, brain - cerebellum, brain - hippocampus, brain - substantia nigra, brain - thalamus, brain -whole, fetal brain, fetal kidney, fetal liver, fetal lung, heart, kidney, lymphoma - Raji, mammary gland, pancreas, pituitary gland, placenta, prostate, salivary gland, skeletal muscle, small intestine, spinal cord, spleen, stomach, testis, thyroid, trachea, uterus. Usually the resulting amplicons were gel purified, cloned and sequenced to high redundancy. The resulting sequences from all clones were assembled with themselves, with other fragments in CuraGen Corporation's database and with public ESTs. Fragments and ESTs were included as components for an assembly when the extent of their identity with another component ofthe assembly was at least 95% over 50 bp. In addition, sequence traces were evaluated manually and edited for corrections if appropriate. These procedures provide the sequence reported below, which is designated MOLlb, or alternatively Accession Number CG56250-02. This differs from the previously identified sequence in lacking 996 internal amino acids in addition to a few minor changes.

A disclosed Notch-like nucleic acid of 6728 nucleotides, MOLl b, is shown in Table IC. The disclosed MOLlb open reading frame ("ORF") begins at the ATG initiation codon at nucleotides 13-15, and terminates at a TGA codon at nucleotides 4431- 4434. In Table 1 D the start and stop codons are in bold letters, and the untranslated regions are underlined.

Table ID. MOLlb nucleotide sequence (SEQ ID NO:3).

TCATCTGGAATTATGCCCGCCCTGCGCCCCGCTCTGCTGTGGGCGCTGCTGGCGCTCTGGCTGTGCTGCGCGGCCCC CGCGCATGCATTGCAGTGTCGAGATGGCTATGAACCCTGTGTAAATGAAGGAATGTGTGTTACCTACCACAATGGCA CAGGATACTGCAAATGTCCAGAAGGCTTCTTGGGGGAATATTGTCAACATCGAGACCCCTGTGAGAAGAACCGCTGC CAGAATGGTGGGACTTGTGTGGCCCAGGCCATGCTGGGGAAAGCCACGTGCCGATGTGCCTCAGGGTTTACAGGAGA GGACTGCCAGTACTCAACATCTCATCCATGCTTTGTGTCTCGACCCTGCCTGAATGGCGGCACATGCCATATGCTCA GCCGGGATACCTATGAGTGCACCTGTCAAGTCGGGTTTACAGGTAAGGAGTGCCAATGGACGGATGCCTGCCTGTCT CATCCCTGTGCAAATGGAAGTACCTGTACCACTGTGGCCAACCAGTTCTCCTGCAAATGCCTCACAGGCTTCACAGG GCAGAAATGTGAGACTGATGTCAATGAGTGTGACATTCCAGGACACTGCCAGCATGGTGGCACCTGCCTCAACCTGC CTGGTTCCTACCAGTGCCAGTGCCCTCAGGGCTTCACAGGCCAGTACTGTGACAGCCTGTATGTGCCCTGTGCACCC TCACCTTGTGTCAATGGAGGCACCTGTCGGCAGACTGGTGACTTCACTTTTGAGTGCAACTGCCTTCCAGGTTTTGA AGGGAGCACCTGTGAGAGGAATATTGATGACTGCCCTAACCACAGGTGTCAGAATGGAGGGGTTTGTGTGGATGGGG TCAACACTTACAACTGCCGCTGTCCCCCACAATGGACAGGACAGTTCTGCACAGAGGATGTGGATGAATGCCTGCTG CAGCCCAATGCCTGTCAAAATGGGGGCACCTGTGCCAACCGCAATGGAGGCTATGGCTGTGTATGTGTCAACGGCTG GAGTGGAGATGACTGCAGTGAGAACATTGATGATTGTGCCTTCGCCTCCTGTACTCCAGGCTCCACCTGCATCGACC GTGTGGCCTCCTTCTCTTGCATGTGCCCAGAGGGGAAGGCAGGTCTCCTGTGTCATCTGGATGATGCATGCATCAGC AATCCTTGCCACAAGGGGGCACTGTGTGACACCAACCCCCTAAATGGGCAATATATTTGCACCTGCCCACAAGGCTA CAAAGGGGCTGACTGCACAGAAGATGTGGATGAATGTGCCATGGCCAATAGCAATCCTTGTGAGCATGCAGGAAAAT GTGTGAACACGGATGGCGCCTTCCACTGTGAGTGTCTGAAGGGTTATGCAGGACCTCGTTGTGAGATGGACATCAAT GAGTGCCATTCAGACCCCTGCCAGAATGATGCTACCTGTCTGGATAAGATTGGAGGCTTCACATGTCTGTGCATGCC AGGTTTCAAAGGTGTGCATTGTGAATTAGAAATAAATGAATGTCAGAGCAACCCTTGTGTGAACAATGGGCAGTGTG TGGATAAAGTCAATCGTTTCCAGTGCCTGTGTCCTCCTGGTTTCACTGGGCCAGTTTGCCAGATTGATATTGATGAC TGTTCCAGTACTCCGTGTCTGAATGGGGCAAAGTGTATCGATCACCCGAATGGCTATGAATGCCAGTGTGCCACAGG TTTCACTGGTGTGTTGTGTGAGGAGAACATTGACAACTGTGACCCCGATCCTTGCCACCATGGTCAGTGTCAGGATG GTATTGATTCCTACACCTGCATCTGCAATCCCGGGTACATGGGCGCCATCTGCAGTGACCAGATTGATGAATGTTAC AGCAGCCCTTGCCTGAACGATGGTCGCTGCATTGACCTGGTCAATGGCTACCAGTGCAACTGCCAGCCAGGCACGTC AGGGGTTAATTGTGAAATTAATTTTGATGACTGTGCAAGTAACCCTTGTATCCATGGAATCTGTATGGATGGCATTA ATCGCTACAGTTGTGTCTGCTCACCAGGATTCACAGGGCAGAGATGTAACATTGACATTGATGAGTGTGCCTCCAAT CCCTGTCGCAAGGGTGCAACATGTATCAACGGTGTGAATGGTTTCCGCTGTATATGCCCCGAGGGACCCCATCACCC CAGCTGCTACTCACAGGTGAACGAATGCCTGAGCAATCCCTGCATCCATGGAAACTGTACTGGAGGTCTCAGTGGAT ATAAGTGTCTCTGTGATGCAGGCTGGGTTGGCATCAACTGTGAAGTGGACAAAAATGAATGCCTTTCGAATCCATGC CAGAATGGAGGAACTTGTGACAATCTGGTGAATGGATACAGGTGTACTTGCAAGAAGGGCTTTAAAGGCTATAACTG CCAGGTGAATATTGATGAATGTGCCTCAAATCCATGCCTGAACCAAGGAACCTGCTTTGATGACATAAGTGGCTACA CTTGCCACTGTGTGCTGCCATACACAGGCAAGAATTGTCAGACAGTATTGGCTCCCTGTTCCCCAAACCCTTGTGAG AATGCTGCTGTTTGCAAAGAGTCACCAAATTTTGAGAGTTATACTTGCTTGTGTGCTCCTGGCTGGCAAGGTCAGCG GTGTACCATTGACATTGACGAGTGTATCTCCAAGCCCTGCATGAACCATGGTCTCTGCCATAACACCCAGGGCAGCT ACATGTGTGAATGTCCACCAGGCTTCAGTGGTATGGACTGTGAGGAGGACATTGATGACTGCCTTGCCAATCCTTGC CAGAATGGAGGTTCCTGTATGGATGGAGTGAATACTTTCTCCTGCCTCTGCCTTCCGGGTTTCACTGGGGATAAGTG CCAGACAGACATGAATGAGTGTCTGAGTGAACCCTGTAAGAATGGAGGGACCTGCTCTGACTACGTCAACAGTTACA CTTGCAAGTGCCAGGCAGGATTTGATGGAGTCCATTGTGAGAACAACATCAATGAGTGCACTGAGAGCTCCTGTTTC AATGGTGGCACATGTGTTGATGGGATTAACTCCTTCTCTTGCTTGTGCCCTGTGGGTTTCACTGGATCCTTCTGCCT CCATGAGATCAATGAATGCAGCTCTCATCCATGCCTGAATGAGGGAACGTGTGTTGATGGCCTGGGTACCTACCGCT GCAGCTGCCCCCTGGGCTACACTGGGAAAAACTGTCAGACCCTGGTGAATCTCTGCAGTCGGTCTCCATGTAAAAAC AAAGGTACTTGTGTTCAGAAAAAAGCAGAGTCCCAGTGCCTATGTCCATCTGGATGGGCTGGTGCCTATTGTGACGT GCCCAATGTCTCTTGTGACATAGCAGCCTCCAGGAGAGGTGTGCTTGTTGAACACTTGTGCCAGCACTCAGGTGTCT GCATCAATGCTGGCAACACGCATTACTGTCAGTGCCCCCTGGGCTATACTGGGAGCTACTGTGAGGAGCAACTCGAT GAGTGTGCGTCCAACCCCTGCCAGCACGGGGCAACATGCAGTGACTTCATTGGTGGATACAGATGCGAGTGTGTCCC AGGCTATCAGGGTGTCAACTGTGAGTATGAAGTGGATGAGTGCCAGAATCAGCCCTGCCAGAATGGAGGCACCTGTA TTGACCTTGTGAACCATTTCAAGTGCTCTTGCCCACCAGGCACTCGGGGCCTACTCTGTGAAGAGAACATTGATGAC TGTGCCCGGGGTCCCCATTGCCTTAATGGTGGTCAGTGCATGGATAGGATTGGAGGCTACAGTTGTCGCTGCTTGCC TGGCTTTGCTGGGGAGCGTTGTGAGGGAGACATCAACGAGTGCCTCTCCAACCCCTGCAGCTCTGAGGGCAGCCTGG ACTGTATACAGCTCACCAATGACTACCTGTGTGTTTGCCGTAGTGCCTTTACTGGCCGGCACTGTGAAACCTTCGTC GATGTGTGTCCCCAGATGCCCTGCCTGAATGGAGGGACTTGTGCTGTGGCCAGTAACATGCCTGATGGTTTCATTTG CCGTTGTCCCCCGGGATTTTCCGGGGCAAGGTACCAGATTCCAGAAATGGCCCGTTTGCCCAGTGTGGCTTTCCCCA CTGCCATGATGCCCCAGCAGGACGGGCAGGTAGCTCAGACCATTCTCCCAGCCTATCATCCTTTCCCAGCCTCTGTG GGCAAGTACCCCACACCCCCTTCACAGCACAGTTATGCTTCCTCAAATGCTGCTGAGCGAACACCCAGTCACAGTGG TCACCTCCAGGGTGAGCATCCCTACCTGACACCATCCCCAGAGTCTCCTGACCAGTGGTCAAGTTCATCACCCCACT CTGCTTCTGACTGGTCAGATGTGACCACCAGCCCTACCCCTGGGGGTGCTGGAGGAGGTCAGCGGGGACCTGGGACA CACATGTCTGAGCCACCACACAACAACATGCAGGTTTATGCGTGAGAGAGTCCACCTCCAGTGTAGAGACATAACTG ACTTTTGTAAATGCTGCTGAGGAACAAATGAAGGTCATCCGGGAGAGAAATGAAGAAATCTCTGGAGCCAGCTTCTA GAGGTAGGAAAGAGAAGATGTTCTTATTCAGATAATGCAAGAGAAGCAATTCGTCAGTTTCACTGGGTATCTGCAAG GCTTATTGATTATTCTAATCTAATAAGACAAGTTTGTGGAAATGCAAGATGAATACAAGCCTTGGGTCCATGTTTAC τCTCTTCTATTTGGAGAATAAGATGGATGCTTATTGAAGCCCAGACATTCTTGCAGCTTGGACTGCATTTTAAGCCC TGCAGGCTTCTGCCATATCCATGAGAAGATTCTACACTAGCGTCCTGTTGGGAATTATGCCCTGGAATTCTGCCTGA ATTGACCTACGCATCTCCTCCTCCTTGGACATTCTTTTGTCTTCATTTGGTGCTTTTGGTTTTGCACCTCTCCGTGA TTGTAGCCCTACCAGCATGTTATAGGGCAAGACCTTTGTGCTTTTGATCATTCTGGCCCATGAAAGCAACTTTGGTC TCCTTTCCCCTCCTGTCTTCCCGGTATCCCTTGGAGTCTCACAAGGTTTACTTTGGTATGGTTCTCAGCACAAACCT TTCAAGTATGTTGTTTCTTTGGAAAATGGACATACTGTATTGTGTTCTCCTGCATATATCATTCCTGGAGAGAGAAG GGGAGAAGAATACTTTTCTTCAACAAATTTTGGGGGCAGGAGATCCCTTCAAGAGGCTGCACCTTAATTTTTCTTGT CTGTGTGCAGGTCTTCATATAAACTTTACCAGGAAGAAGGGTGTGAGTTTGTTGTTTTTCTGTGTATGGGCCTGGTC AGTGTAAAGTTTTATCCTTGATAGTCTAGTTACTATGACCCTCCCCACTTTTTTAAAACCAGAAAAAGGTTTGGAAT GTTGGAATGACCAAGAGACAAGTTAACTCGTGCAAGAGCCAGTTACCCACCCACAGGTCCCCCTACTTCCTGCCAAG CATTCCATTGACTGCCTGTATGGAACACATTTGTCCCAGATCTGAGCATTCTAGGCCTGTTTCACTCACTCACCCAG CATATGAAACTAGTCTTAACTGTTGAGCCTTTCCTTTCATATCCACAGAAGACACTGTCTCAAATGTTGTACCCTTG CCATTTAGGACTGAACTTTCCTTAGCCCAAGGGACCCAGTGACAGTTGTCTTCCGTTTGTCAGATGATCAGTCTCTA CTGATTATCTTGCTGCTTAAAGGCCTGCTCACCAATCTTTCTTTCACACCGTGTGGTCCGTGTTACTGGTATACCCA GTATGTTCTCACTGAAGACATGGACTTTATATGTTCAAGTGCAGGAATTGGAAAGTTGGACTTGTTTTCTATGATCC AAAACAGCCCTATAAGAAGGTTGGAAAAGGAGGAACTATATAGCAGCCTTTGCTATTTTGTGCTACCATTTCTTTTC CTCTGAAGCGGCCATGACATTCCCTTTGGCAACTAACGTAGAAACTCAACAGAACATTTTCCTTTCCTAGAGTCACC TTTTAGATGATAATGGACAACTATAGACTTGCTCATTGTTCAGACTGATTGCCCCTCACCTGAATCCACTCTCTGTA TTCATGCTCTTGGCAATTTCTTTGACTTTCTTTTAAGGGCAGAAGCATTTTAGTTAATTGTAGATAAAGAATAGTTT TCTTCCTCTTCTCCTTGGGCCAGTTAATAATTGGTCCATGGCTACACTGCAACTTCCGTCCAGTGCTGTGATGCCCA TGACACCTGCAAAATAAGTTCTGCCTGGGCATTTTGTAGATATTAACAGGTGAATTCCCGACTCTTTTGGTTTGAAT GACAGTTCTCATTCCTTCTATGGCTGCAAGTATGCATCAGTGCTTCCCACTTACCTGATTTGTCTGTCGGTGGCCCC ATATGGAAACCCTGCGTGTCTGTTGGCATAATAGTTTACAAATGGTTTTTTCAGTCCTATCCAAATTTATTGAACCA ACAAAAATAATTACTTCTGCCCTGAGATAAGCAGATTAAGTTTGTTCATTCTCTGCTTTATTCTCTCCATGTGGCAA CATTCTGTCAGCCTCTTTCATAGTGTGCAAACATTTTATCATTCTAAATGGTGACTCTCTGCCCTTGGACCGATTTA TTATTCACAGATGGGGAGAACCTATCTGCATGGACCCTCACCATCCTCTGTGCAGCACACACAGTGCAGGGAGCCAG TGGCGATGGCGATGACTTTCTTCCCCTGG

The protein encoded by the MOLlb nucleic acid sequence has 2469 amino acid residues, and is disclosed in Table IE. The MOLlb protein was analyzed for signal peptide prediction and cellular localization. SignalP results predict that MOLlb is cleaved between position 25 and 26 (AHA-LQ) of SEQ ID NO:4. Psort and Hydropathy profiles also predict that MOLlb contains a signal peptide and is likely to be localized extracellularly (Certainty=0.7666).

Table IE. Encoded MOLlb protein sequence (SEQ ID NO:4).

MPALRPALLWALLA CCAAPAHALQCRDGYEPCVWEGMCVTYHNGTGYCKCPEGFLGEYCQHRDPCEKNRCQNGG TCVAQAMLGKATCRCASGFTGEDCQYSTSHPCFVSRPC NGGTCHMLSRDTYECTCQVGFTGKECQ TDACLSHPCA NGSTCTTVANQFSCKCLTGFTGQKCETDVNECDIPGHCQHGGTCLNLPGSYQCQCPQGFTGQYCDSLYVPCAPSPCV NGGTCRQTGDFTFECNCLPGFEGSTCERNIDDCPNHRCQNGGVCVDGVNTYNCRCPPQ TGQFCTEDVDECLLQPNA CQNGGTCANRNGGYGCVCVNG SGDDCSENIDDCAFASCTPGSTCIDRVASFSCMCPEGKAGL CHLDDACISNPCH KGALCDTNPLNGQYICTCPQGYKGADCTEDVDECAMANSNPCEHAGKCVNTDGAFHCEC KGYAGPRCEMDINECHS DPCQNDATCLDKIGGFTCLC PGF GVHCELEINECQSNPCVMNGQCVD VNRFQC CPPGFTGPVCQIDIDDCSST PC NGAKCIDHPNGYECQCATGFTGV CEENIDNCDPDPCHHGQCQDGIDSYTCICNPGYMGAICSDQIDECYSSPC LNDGRCIDLVNGYQCNCQPGTSGV CEINFDDCASNPCIHGICMDGINRYSCVCSPGFTGQRCNIDIDECASNPCRK GATCINGΛ7NGFRCICPEGPHHPSCYSQV ECLSNPCIHGNCTGGLSGYKCLCDAG VGINCEVDKNECLSNPCQNGG TCDNLVNGYRCTCKKGFKGYNCQVNIDECASNPCLNQGTCFDDISGYTCHCVLPYTGNCQTV APCSPNPCENAAV CKESPNFESYTCLCAPGWQGQRCTIDIDECISKPCMNHG CHNTQGSYMCECPPGFSGMDCEEDIDDCLANPCQNGG SC DGΛ7 TFSCLCLPGFTGDKCQTDMNECLSEPCKNGGTCSDYVNSYTCKCQAGFDGVHCENNINECTESSCFNGGT CVDGINSFSCLCPVGFTGSFCLHEINECSSHPCLNEGTCVDGLGTYRCSCPLGYTGKNCQTLVN CSRSPCK KGTC VQKKAESQC CPSG AGAYCDVPNVSCDIAASRRGVLVEHLCQHSGVCINAGNTHYCQCPLGYTGSYCEEQLDECAS NPCQHGATCSDFIGGYRCECVPGYQGVNCEYEVDECQNQPCQNGGTCIDLVNHFKCSCPPGTRGLLCEENIDDCARG PHC NGGQCMDRIGGYSCRCLPGFAGERCEGDINECLSNPCSSEGSLDCIQLTNDY CVCRSAFTGRHCETFVDVCP QMPCLNGGTCAVASNMPDGFICRCPPGFSGARYQIPEMARLPSVAFPTAMMPQQDGQVAQTILPAYHPFPASVGKYP TPPSQHSYASSNAAERTPSHSGHLQGEHPYLTPSPESPDQWSSSSPHSASD SDVTTSPTPGGAGGGQRGPGTHMSE PPHM1SIMQVYA A region ofthe MOLlb nucleic acid sequence, localized to chromosome 1, has 4041 of 4042 bases (99%) identical to a gb:GENBANK-ID:AF308601 |acc:AF308601.1 mRNA from Homo sapiens (Homo sapiens NOTCH 2 (N2) mRNA, complete eds), with an E-value of 0.0.

The amino acid sequence of MOLlb has 1340 of 1343 amino acid residues (99%) identical to, and 1340 of 1343 amino acid residues (99%) similar to, the 2471 amino acid residue ptnr:TREMBLNEW-ACC:AAG37073 protein from Homo sapiens (Human) (NOTCH2 PROTEIN).

MOLlb expressed in at least the following tissues: adrenal gland, bone marrow, brain - amygdala, brain - cerebellum, brain - hippocampus, brain - substantia nigra, brain - thalamus, brain -whole, fetal brain, fetal kidney, fetal liver, fetal lung, heart, kidney, lymphoma - Raji, mammary gland, pancreas, pituitary gland, placenta, prostate, salivary gland, skeletal muscle, small intestine, spinal cord, spleen, stomach, testis, thyroid, trachea, uterus, Aorta, Ascending Colon, Bone, Cartilage, Cochlea, Colon, Coronary Artery, Epidermis, Foreskin, Liver, Lung, Lymph node, Lymphoid tissue, Muscle, Nasoepithelium, Ovary, Parathyroid Gland, Parotid Salivary glands, Peripheral Blood, Respiratory Bronchiole, Retina, Synovium/Synovial membrane, Thymus, Tonsils, Umbilical Vein, Vein, Whole Organism.

One or more consensus positions (Cons. Pos.) ofthe nucleotide sequence of MOLlb have been identified as single nucleotide polymorphisms (SNPs) as shown in Table I F. "Depth" represents the number of clones covering the region ofthe SNP. The Putative Allele Frequency (PAF) is the fraction of all the clones containing the SNP. A dash ("-"), when shown, means that a base is not present. The sign ">" means "is changed to".

The amino acid sequence of MOLla also had high homology to other proteins as shown in table 1 G.

A ClustalW analysis comparing disclosed proteins ofthe invention with related OR protein sequences is given in Table I H, with MOLla shown on line 1 and MOLl b on line 2.

In the ClustalW alignment ofthe MOLla and MOLlb proteins, as well as all other ClustalW analyses herein, the black outlined amino acid residues indicate regions of conserved sequence (i.e., regions that may be required to preserve structural or functional properties), whereas non-highlighted amino acid residues are less conserved and can potentially be mutated to a much broader extent without altering protein structure or function. Residue differences between any MOLX variant sequences herein are written to show the residue in the "a" variant and the residue position with respect to the "a" variant. MOL residues in all following sequence alignments that differ between the individual MOL variants are highlighted with a box and marked with the (o) symbol above the variant residue in all alignments herein. Table IH. ClustalW Analysis of MOLla

1) Novel MOLla (SEQ ID NO.-2)

2) Novel MOLlb (SEQ ID NO : 4 )

3) gi|lθ I252|pir| ]A35844 Xotch protein African clawed frog (SEQ ID

NO: 25)

4) gi|66 79096 |ref |NP_032742. I| Notch gene homolog 3, (Drosophila) [Mus musculus ] (SEQ ID NO: 26)

5) gi|l3 242247|ref |NP_077334.l| Notch gene homolog 2, (Drosophila) [Rattus norvegicus] (SEQ ID NO: 27)

6) gi|22 09059 [dbj |BAA20535. l| Notch 2 [Takifugu rubripes] (SEQ ID NO: 28)

7) gi | 6093542 |sp[Q07008 |NTC1_RAT NEUROGENIC LOCUS NOTCH HOMOLOG PROTEIN 1 PRECURSOR (SEQ ID NO: 29)

210 220 230 240 90

o

H U α.

gi|6093542| EgγSD!3 SLlES5 M§H!^j^_|Ai__, DS MBigSaDBA - ϊ

MOLla MOLlb

oi oi oi oi oi

> o o o o

IQ IQ IQ IQ IQ IQ IQ IQ IQ IQ g IQ CQ (Q (Q (Q g IQ IQ IQ (fl CQ ⁽Q IQ IQ IQ IQ g g g IQ 10 (Q (Q (Q μ- μ- μ- μ- μ- o μ. μ. μ. μ. μ. g o o μ- μ- μ- μ- μ- O 0 O t-ⁱ F oi u μ m p t (ri l-ⁱ l-ⁱ

H H I-¹ H

0" (u o t to CO o t to rr P> tr

ID O t ~J ID O tO -J il- ID O tO vo o t -J *» vo t

CO vo rf- vo to vo . vo t CO VO rf- VO t to Vo ifc. vo t to vo f *. o to tπ o to o cn tπ o to o tπ tπ o to o tπ tπ t ro- *. tπ * i*- Lπ to vo to > tπ to vo to il- tπ to vo to φ. tπ to o to to vo ifc. σi — to VO Ifc. CO t 10 it* co — t vo *. ~J — —

2S50 1860 1870 1880

MOLla NLlGTGTSEHgjvgD@-GPQPKKV A§DEALLSEE|2DPlf»JR

MOLlb gi|l04252 | SFMDDNQNE gi|6679096| ESLMGEWTDL: Έ E gij 13242247 I NLIGSTTSEHSGgDl-GPQPKKAKAraDDEALLSESDPVS] gi|2209059| Aλπ,DGGQSQRSLEDg-VPPR PRLΞGKPLLPMAM§GGV§] gi|6093542 ALMDDNQNE -fgGyjJED - LETKKFRFE^P WLPDL -jDQTgH

2090 2100 2110 2120

MOLla

MOLlb ^^S ^^^ ^ S^M>mS sm^ S

gi| 6093542 I

2250 2260 2270 2280

MOLla KSLSEKVQLS-ES fVTLSPVDSLESPHTYVSDTTSSPMIT

MOLlb g 1104252 | SQDGKTTLLDSGS^GVLSPVDSLESTHGYLSDVSSPPLMT gij 6679096 | LTLA gij 13242247 I KCLNEKVQLS-ES|f VTLSPVDSLESPHTYVSDATSSPM1T giJ2209059| KPTG--VEGP-GA AGAG- -G AIGGTAANGVN gij 609354 j SQDGKGCLLD--S SMLSPVDSLESPHGYLSDVASPPLLP

2290 2300 2310 2320

MOLla S |GILQASPNPMLATAA PAPVHAQHALSFSNLHEMQPL-

MOLlb gi 1104252 I S|FQQΞPSMPLNHLTSM ESQLGMNHINMATKQEMAAGS- giJ6679096] C G PLADSSVTLSPVDSLDSPRPFSGP - gij 13242247 I S|GILQASPTP-LLAAA AAPVHAQHALSFSNLHEMQPL- gij₂209059| NGV TAG AL ESSVTMSPVDSLESPHSFLGD- g j 6093542 S |FQQSPSMPLSHLPGMJI DTHLGISHLNVAAKPEMAALAG 50 2360 SGSAGSLSR GSMHFTVJsG -ASRAGPLSR SGSAGSLIR

TGAMNFTVgA

2370 2380 2390 2400

MOLla LHPVPVPAD^SINRMEVNETQYNEMFGMVLAPAV-GH--PS MOLlb gi 1104252 I APTMNSQCD jLAR--LQNGMVQNQYDPϊRNGIQQGN-AQQ gi| 6679096| Q PGG gi] 13242247 I LHSVPVPSDSMNRVEMSETQYSEMFGMVLAPAEGTH--PG gi|2209059| QQ G-1VG--TT HPYSDHMFSLIPHQIGGSH--TG gi| 6093542 j PASLNGQCE |LPR- -LQNGMVPSQYNPLRPGVTPGTLSTQ

2420 2420 2430 2440

MOLla WHSSPERPPEG HITTPREPgp|lVTF0LIPKG-

MOLlb gi 1104252 I AQALQHGLMTSLHNGLPATTJLSQMMTYGJAMPNTRLANQPH gij 6679096] -CVLSFGLLNPVAVPLD AR P| gij 13242247 I MAAPQSRAPEGKPIPTQREPSP| IVTFSILIPKG giJ2209059| MGHSRGPMFTPMNVTMSREQ3PYIVTFGMMAPGGGQGMLK gij 6093542 I AAGLQHGMMGPIHSSLSTNτ3s§II-γfgGLPNTRLATQPH

2450 2460 2470 2480

MOLla SIA QPAGAPQPQSTCPPAVAGPLP

MOLlb

LMQAQQMQQQ QNLQLHQSMQQQHHNSSTTSTHINSP I SLA- - -QAAGAPQTQSGCPPAVAGPLP

QSQTGQVQVT- QSQNQSHSQQG-PGHLHCAQS

LVQTQQVQPQNLQIQPQNLQPPSQPHLSVSSAANGHLGRS

2610 2620 2630

MOLla AGGGQRG GTHMΞEIPHNNMQVYA-

MOLlb AGGGQRG|GTHMSE@PHNNMQVYA- gi 1104252 I TSMQPQ_RTHIBEAFK gij 6679096] ASGALPAQPHPISVPSLPQSQTQLGPQSEVTPKRQVMA gij 13242247 I GGGGQRG|GTHMSE!PHSNMQVYA- giJ2209059| THCRLHTAHTFQSRCSCSPS NRFSRA1SSLSWGTCR- gi] 6093542 — - TSM SQITHI@EAFK - When the sequences ofthe invention are referred to as MOLl, this refers to the sequences disclosed as MOLla and MOLlb.

The presence of identifiable domains in MOLl, as well as all other MOLX proteins, was determined by searches using software algorithms such as P OSITE, DOMAIN, Blocks, Pfam, ProDomain, and Prints, and then determining the Interpro number by crossing the domain match (or numbers) using the Interpro website (http:www.ebi.ac.uk/ interpro). DOMAIN results, e.g., for MOLl as disclosed in Table II, were collected from the Conserved Domain Database (CDD) with Reverse Position Specific BLAST analyses. This BLAST analysis software samples domains found in the Smart and Pfam collections. For Table II and all successive DOMAIN sequence alignments, fully conserved single residues are indicated by black shading and "strong" semi-conserved residues are indicated by grey shading. The "strong" group of conserved amino acid residues may be any one ofthe following groups of amino acids: STA, NEQK, NHQK, NDEQ, QHRK, MILV, MILF, HY, FYW. Tables II- IN list the domain description from DOMAIN analysis results against

MOLl . The region from amino acid residue 1416 through 1454 (SEQ ID NO:2) most probably (E = l e^"6) contains a domain found in Notch and Lin- 12, aligned here in table II. Notch and Lin- 12 are both involved in organismal development, cell cycle, and apoptosis. The region from amino acid residue 1504 through 1532 (SEQ ID NO:2) most probably (E = 2e^"4) also contains a domain found in Notch and Lin- 12, aligned here in table 1 J. The region from amino acid residue 1875 through 1906 (SEQ ID NO:2) most probably (E = 6e^{" 3}) contains an Ank repeat, aligned here in table IK. Ank repeats are markers for the protein ankyrin which is involved in cell adhesion and contact inhibition. The region from amino acid residue 1974 through 2006 (SEQ ID NO:2) most probably (E = 2e^"4) also contains an Ank repeat, aligned here in table IL. The region from amino acid residue 182 through 215 (SEQ ID NO:2) most probably (E = le^"4) contains a Calcium binding EGF- like domain, aligned here in table 1M. EGF is a growth factor that modulates the proliferation of many cell types. The region from amino acid residue 872 through 908 (SEQ ID NO:2) most probably (E = 9e^" ) also contains a Calcium binding EGF-like domain, aligned here in table IN. This indicates that the MOLl sequence has properties similar to those of other proteins known to contain these domains. Table II. Domain Analysis of MOLl gnl I Smart 1 smart00004, NL, Domain found in Notch and Lin-12; The Notch protein is essential for the proper differentiation of the Drosophila ectoderm. This protein contains 3 NL domain CD-Length = 39 residues, 100.0% aligned Score = 50.1 bits (118), Expect = le-06

Table IK. Domain Analysis of MOLl gnl ] Pfam]pfam00023 , ank, Ank repeat

CD-Length = 33 residues, 97.0% aligned

Score = 44.7 bits (104), Expect = 6e-05

M0L1_7

Smart | smart00179 (SEQ ID NO : 87 )

MOLl_8 B Smart] smart00179 B (SEQ ID NO:88)

Uses of the Compositions of the Invention

The protein similarity information, expression pattern, cellular localization, and map location for the protein and nucleic acid disclosed herein suggest that MOLl may have important structural and/or physiological functions characteristic ofthe EGF-like domain containing protein family. Therefore, the nucleic acids and proteins ofthe invention are useful in potential diagnostic and therapeutic applications and as a research tool. These include serving as a specific or selective nucleic acid or protein diagnostic and/or prognostic marker, wherein the presence or amount ofthe nucleic acid or the protein are to be assessed. These also include potential therapeutic applications such as the following: (i) a protein therapeutic, (ii) a small molecule drug target, (iii) an antibody target (therapeutic, diagnostic, drug targeting/cytotoxic antibody), (iv) a nucleic acid useful in gene therapy (gene delivery/gene ablation), (v) an agent promoting tissue regeneration in vitro and in vivo, and (vi) a biological defense weapon.

The MOLl nucleic acids and proteins have applications in the diagnosis and/or treatment of various diseases and disorders. For example, the compositions of MOLl may have efficacy for the treatment of patients suffering from endometriosis, fertility disorders, cancer, hypercoagulation, idiopathic thrombocytopenic purpura, immunodeficiencies, systemic lupus erythematosus, asthma, emphysema, scleroderma, allergy, ARDS, Von Hippel-Lindau (VHL) syndrome, Alzheimer's disease, stroke, tuberous sclerosis, hypercalceimia, Parkinson's disease, Huntington's disease, cerebral palsy, epilepsy, multiple sclerosis, ulcers, ataxia-telangiectasia, leukodystrophies, behavioral disorders, addiction, anxiety, pain, neuroprotection, osteoporosis, hypercalceimia, arthritis, ankylosing spondylitis, scoliosis, diabetes, autoimmune disease, myasthenia gravis, muscular dystrophy, renal artery stenosis, interstitial nephritis, glomerulonephritis, polycystic kidney disease, systemic lupus erythematosus, renal tubular acidosis, IgA nephropathy, hypercalceimia, Lesch-Nyhan syndrome, developmental disorders, growth disorders, and/or wounds, as well as other diseases, disorders and conditions. The reactivation ofthe Notch signaling pathway during wound healing has been demonstrated and the similarity between developmental and regenerative processes has been suggested (Exp Cell Res 1999 Feb l;246(2):312-8).

These materials are further useful in the generation of antibodies that bind immuno-specifically to the novel MOLl substances for use in therapeutic or diagnostic methods. These antibodies may be generated according to methods known in the art, using prediction from hydrophobicity charts, as described in the "Anti-MOLX Antibodies" section below. The disclosed MOLl protein has multiple hydrophilic regions, each of which can be used as an immunogen. In one embodiment, a contemplated MOLl epitope is from about amino acids 10 to 150. In another embodiment, a MOLl epitope is from about amino acids 160 to 190. In additional embodiments, MOLl epitopes are from about amino acids 195 to 350, 400 to 525, 550 to 575, 590 to 600, 610 to 650, 780 to 880, 900 to 1000, 1100 to 1150, 1175 to 1200, 1225 to 1300, and from about amino acids 1380 to 1500. These novel proteins can also be used to develop assay systems for functional analysis.

MOL2

MOL2a

MOL2a is a novel insulin-like growth factor binding protein-like protein. The novel nucleic acid of 2631 nucleotides, (SC98428706_EXT, SEQ ID NO:5) encoding a novel insulin-like growth factor binding protein-like protein is shown in Table 2A. The start and stop codons are in bold. Table 2A. MOL2a Nucleotide Sequence (SEQ ID NO:5) TGATTTACATACAAGTAATTTTTCAAGTAATGACCATTGAAAAAATGTTTTCTTTTTATTTTTTAGATTATTTCTC TTTATTCAGAAGCATACAGTTGTTTGCTGATTGCAAGAAGATGTTTCTGTGGCTGTTTCTGATTTTGTCAGCCCTGA TTTCTTCGACAAATGCAGATTCTGACATATCGGTGGAAATTTGCAATGTGTGTTCCTGCGTGTCAGTTGAGAATGTG CTCTATGTCAACTGTGAGAAGGTTTCAGTCTACAGACCAAATCAGCTGAAACCACCTTGGTCTAATTTTTATCACCT CAATTTCCAAAATAATTTTTTAAATATTCTGTATCCAAATACATTCTTGAATTTTTCACATGCAGTCTCCCTGCATC TGGGGAATAATAAACTGCAGAACATTGAGGGAGGAGCCTTTCTTGGGCTCAGTGCATTAAAGCAGTTGCACTTGAAC AACAATGAATTAAAGATTCTCCGAGCTGACACTTTCCTTGGCATAGAGAACTTGGAGTATCTCCAGGCTGACTACAA TTTAATCAAGTATATTGAACGAGGAGCCTTCAATAAGCTCCACAAACTGAAAGTTCTCATTCTTAATGACAATCTGA TTTCATTCCTTCCTGATAATATTTTCCGATTCGCATCTTTGACCCATCTGGATATACGAGGGAACAGAATCCAGAAG CTCCCTTATATCGGGGTTCTGGAACACATTGGCCGTGTCGTTGAATTGCAACTGGAAGATAACCCTTGGAACTGTAG CTGTGATTTATTGCCCTTAAAAGCTTGGCTGGAGAACATGCCATATAACATTTACATAGGAGAAGCTATCTGTGAAA CTCCCAGTGACTTATATGGAAGGCTTTTAAAAGAAACCAACAAACAAGAGCTATGTCCCATGGGCACCGGCAGTGAT TTTGACGTGCGCATCCTGCCTCCATCTCAGCTGGAAAATGGCTACACCACTCCCAATGGTCACACTACCCAAACATC TTTACACAGATTAGTAACTAAACCACCAAAAACAACAAATCCTTCCAAGATCTCTGGAATCGTTGCAGGCAAAGCCC TCTCCAACCGCAATCTCAGTCAGATTGTGTCTTACCAAACAAGGGTGCCTCCTCTAACACCTTGCCCGGCACCTTGC TTCTGCAAAACACACCCTTCAGATTTGGGACTAAGTGTGAACTGCCAAGAGAAAAATATACAGTCTATGTCTGAACT GATACCGAAACCTTTAAATGCGAAGAAGCTGCACGTCAATGGCAATAGCATCAAGGATGTGGACGTATCAGACTTCA CTGACTTTGAAGGACTGGATTTGCTTCATCTAGGCAGCAATCAAATTACAGTGATTAAGGGAGACGTATTTCACAAT CTCACTAATTTACGCAGGCTATATCTCAATGGCAATCAAATTGAGAGACTCTATCCTGAAATATTTTCAGGTCTTCA TAACCTGCAGTATCTGTATTTGGAATACAATTTGATTAAGGAAATCTCAGCAGGCACCTTTGACTCCATGCCAAATT TGCAGTTACTGTACTTAAACAATAATCTCCTAAAGAGCCTGCCTGTTTACATCTTTTCCGGAGCACCCTTAGCTAGA CTGAACCTGAGGAACAACAAATTCATGTACCTGCCTGTCAGTGGGGTCCTTGATCAGTTGCAATCTCTTACACAGAT TGACTTGGAGGGCAACCCATGGGACTGTACTTGTGACTTGGTGGCATTAAAGCTGTGGGTGGAGAAGTTGAGCGACG GGATTGTTGTGAAAGAACTGAAATGTGAGACGCCTGTTCAGTTTGCCAACATTGAACTGAAGTCCCTCAAAAATGAA ATCTTATGTCCCAAACTTTTAAATAAGCCGTCTGCACCATTCACAAGCCCTGCACCTGCCATTACATTCACCACTCC TTTGGGTCCCATTCGAAGTCCTCCTGGTGGGCCAGTGCCTCTGTCTATTTTAATCTTAAGTATCTTAGTGGTCCTCA TTTTAACGGTGTTTGTTGCTTTTTGCCTTCTTGTTTTTGTCCTGCGACGCAACAAGAAACCCACAGTGAAGCACGAA GGCCTGGGGAATCCTGACTGTGGCTCCATGCAGCTGCAGCTAAGGAAGCATGACCACAAAACCAATAAAAAAGATGG ACTGAGCACAGAAGCTTTCATTCCACAAACTATAGAACAGATGAGCAAGAGCCACACTTGTGGCTTGAAAGAGTCAG AAACTGGGTTCATGTTTTCAGATCCTCCAGGACAGAAAGTTGTTATGAGAAATGTGGCCGACAAGGAGAAAGATTTA TTACATGTAGATACCAGGAAGAGACTGAGCACAATTGATGAGCTGGATGAATTATTCCCTAGCAGGGATTCCAATGT GTTTATTCAGAATTTTCTTGAAAGCAAAAAGGAGTATAATAGCATAGGTGTCAGTGGCTTTGAGATCCGCTATCCAG AAAAACAACCAGACAAAAAAAGTAAGAAGTCACTGATAGGTGGCAACCACAGTAAAATTGTTGTGGAACAAAGGAAG AGTGAGTATTTTGAACTGAAGGCGAAACTGCAGAGTTCCCCTGACTACCTACAGGTCCTTGAGGAGCAAACAGCTTT GAACAAGATCTAG

An open reading frame (ORF) for MOL2a was identified from nucleotides 1 to 2628. The disclosed MOL2a polypeptide (SEQ ID NO:6) encoded by SEQ ID NO:5 has 876 amino acid residues and is presented using the one-letter code in Table 2B. The SignalP, Psort and Hydropathy profile ofMOL2a indicate that this sequence does have a signal peptide localized between amino acids 57 and 58 (TNA-DS) and is likely to be localized to the plasma membrane (0.4600 certajnty). Therefore it is likely that MOL2a is available at the appropriate sub-cellular localization and hence accessible for the therapeutic uses described in this application.

Table 2B. Encoded MOL2a protein sequence (SEQ ID NO:6).

MIYIQVIFQVMTIEKMFSFYFLDYFSLFRSIQLFADCKKMFL LFLILSALISSTNADSDISVEICNVCSCVSVENV LYVNCEKVSVYRPNQL PP SNFYHLNFQNNFLNILYPNTFLNFSHAVSLHLGNNKLQNIEGGAFLGLSALKQLHLN NNEL ILRADTFLGIENLEYLQADYNLIKYIERGAFNKLHKLKVLILNDNLISFLPDNIFRFASLTHLDIRGNRIQK LPYIGVLEHIGRWELQLEDNPWNCSCDLLPLKA LENMPYNIYIGEAICETPSDLYGRLLKETNKQELCPMGTGSD FDVRILPPSQLENGYTTPNGHTTQTSLHRLVTKPPKTTNPSKISGIVAGKALSNRNLSQIVSYQTRVPPLTPCPAPC FCKTHPSDLGLSVNCQEKNIQSMSELIPKPLNAKKLHVNGNSIKDVDVSDFTDFEGLDLLHLGSNQITVIKGDVFHN LTNLRRLYLNGNQIERLYPEIFSGLHNLQYLYLEYNLIKEISAGTFDSMPNLQLLYLNNNLLKSLPVYIFSGAPLAR LNLRNNKFMYLPVSGVLDQLQSLTQIDLEGNP DCTCDLVALKLWVEKLSDGIWKELKCETPVQFANIELKSLKNE ILCP LLNKPSAPFTSPAPAITFTTPLGPIRSPPGGPVPLSILILSILWLILTVFVAFCLLVFVLRRNKKPTVKHE GLGNPDCGSMQLQLRKHDHKTNKKDGLSTEAFIPQTIEQMSKSHTCGLKESETGFMFSDPPGQKWMRNVADKEKDL LHVDTRKRLSTIDELDELFPSRDSNVFIQNFLESKKEYNSIGVSGFEIRYPEKQPDKKSKKSLIGGNHSKIWEQRK SEYFELKAKLQSSPDYLQVLEEQTALNKI

The MOL2a nucleic acid sequence, localized on the q26.3-28 region ofthe X chromosome, has 532 of 854 bases (62%) identical to a Homo sapiens Insulin-like growth factor binding protein-like protein mRNA (GENBANK-ID:AB020655|acc:AB020655).

The full amino acid sequence ofthe protein ofthe invention was found to have 318 of 672 amino acid residues (47%) identical to, and 445 of 672 residues (66%) similar to, the 977 amino acid residue Insulin-like growth factor binding protein-like protein from Homo sapiens (SPTREMBL-ACC:094933).

MOL2a expression in different tissues was examined through TaqMan as described below in Example 1.

MOL2b

MOL2b is a novel insulin-like growth factor binding protein-like protein. The novel nucleic acid of 1800 nucleotides, (191999007, SEQ ID NO:101) encoding a novel insulin-like growth factor binding protein-like protein is shown in Table 2C. The start and stop codons are in bold. Since the start and stop codons are not traditional initiation and termination codons, MOL2b could be a partial reading frame that could extend in the 5' and/or 3' directions.

Table 2C. MOL2b Nucleotide Sequence (SEQ ID NO:101)

GGATCCGATTCTGACATATCGGTGGAAATTTGCAATGTGTGTTCCTGCGTGTCAGTTGAGAATGTGCTCTATGTCAA CTGTGAGAAGGTTTCAGTCTACAGACCAAATCAGCTGAAACCACCTTGGTCTAATTTTTATCACCTCAATTTCCAAA ATAATTTTTTAAATATTCTGTATCCAAATACATTCTTGAATTTTTCACATGCAGTCTCCCTGCATCTGGGGAATAAT AAACTGCAGAACATTGAGGGAGGAGCCTTTCTTGGGCTCAGTGCATTAAAGCAGTTGCACTTGAACAACAATGAATT AAAGATTCTCCGAGCTGACACTTTCCCTGGCATAGAGAACTTGGAGTATCTCCAGGCTGACTACAATTTAATCAAGT ATATTGAACGAGGAGCCTTCAATAAGCTCCACAAACTGAAAGTTCTCATTCTTAATGACAATCTGATTTCATTCCTT CCTGATAATATTTTCCGATTCGCATCTTTGACCCATCTGGATATACGAGGGAACAGAATCCAGAAGCTCCCTTATAT CGGGGTTCTGGAACACATTGGCCGTGTCGTTGAATTGCAACTGGAAGATAACCCTTGGAACTGTAGCTGTGATTTAT GCCCTTAAAAGCTTGGCTGGAGAACATGCCATATAACATTTACATAGGAGAAGCTATCTGTGAAACTCCCAGTGAC TTATATGGAAGGCTTTTAAAAGAAACCAACAAACAAGAGCTATGTCCCATGGGCACCGGCAGTGATTTTGACGTGCG CATCCTGCCTCCATCTCAGCTGGAAAATGGCTACACCACTCCCAATGGTCACACTACCCAAACATCTTTACACAGAT TAGTAACTAAACCACCAAAAACAACAAATCCTTCCAAGATCTCTGGAATCGTTGCAGGCAAAGCCCTCTCCAACCGC ATCTCAGTCAGATTGTGTCTTACCAAACAAGGGTGCCTCCTCTAACACCTTGCCCGGCACCTTGCTTCTGCAAAAC ACACCCTTCAGATTTGGGACTAAGTGTGAACTGCCAAGAGAAAAATATACAGTCTATGTCTGAACTGATACCGAAAC CTTTAAATGCGAAGAAGCTGCACGTCAATGGCAATAGCATCAAGGATGTGGACGTATCAGACTTCACTGACTTTGAA GGACTGGATTTGCTTCATTTAGGCAGCAATCAAATTACAGTGATTAAGGGAGACGTATTTCACAATCTCACTAATTT ACGCAGGCTATATCTCAATGGCAATCAAATTGAGAGACTCTATCCTGAAATATTTTCAGGTCTTCATAACCTGCAGT ATCTGTATTTGGAATACAATTTGATTAAGGAAATCTCAGCAGGCACCTTTGACTCCATGCCAAATTTGCAGTTACTG TACTTAAACAATAATCTCCTAAAGAGCCTGCCTGTTTACATCTTTTCCGGAGCACCCTTAGCTAGACTGAACCTGAG GAACAACAAATTCATGTACCTGCCTGTCAGTGGGGTCCTTGATCAGTTGCAATCTCTTACACAGATTGACTTGGAGG GCAACCCATGGGACTGTACTTGTGACTTGGTGGCATTAAAGCTGTGGGTGGGGAAGTTGAGCGACGGGATTGTTGTG AAAGAACTGAAATGTGAGACGCCTGTTCAGTTTGCCAACATTGAACTGAAGTCCCTCAAAAATGAAATCTTATGTCC CAAACTTTTAAATAAGCCGTCTGCACCATTCACAAGCCCTGCACCTACCATTACATTCACCACTCCTTTGGGTCCCA TTCGAAGTCCTCCTGGTGGGCCACTCGAG An open reading frame (ORF) for MOL2b was identified from nucleotides 1 to 1800. The disclosed MOL2b polypeptide (SEQ ID NO: 102) encoded by SEQ ID NO: 101 has 600 amino acid residues and is presented using the one-letter code in Table 2D.

Table 2D. Encoded MOL2b protein sequence (SEQ ID NO:102).

GSDSDISVEICNVCSCVSVENVLYVNCEKVSVYRPNQLKPP SNFYHLNFQNNFLNILYPNTFLNFSHAVSLHLGNN KLQNIEGGAFLGLSALKQLHLNNNELKILRADTFPGIENLEYLQADYNLIKYIERGAFNKLHKLKVLILNDNLISFL PDNIFRFASLTHLDIRGNRIQKLPYIGVLEHIGRWELQLEDNPWNCSCDLLPLKAWLENMPYNIYIGEAICETPSD LYGRLLKETNKQELCPMGTGSDFDVRILPPSQLENGYTTPNGHTTQTSLHRLVTKPPKTTNPSKISGIVAGKALSNR NLSQIVSYQTRVPPLTPCPAPCFCKTHPSDLGLSVNCQEKNIQSMSELIPKPLNAKKLHVNGNSIKDVDVSDFTDFE GLDLLHLGSNQITVIKGDVFHNLTNLRRLYLNGNQIERLYPEIFSGLHNLQYLYLEYNLIKEISAGTFDSMPNLQLL YLNNNLLKSLPVYIFSGAPLARLNLRNNKFMYLPVSGVLDQLQSLTQIDLEGNP DCTCDLVALKLWVGKLSDGIW KELKCETPVQFANIELKSLKNEILCPKLLNKPSAPFTSPAPTITFTTPLGPIRSPPGGPLE

MOL2c

MOL2c is a novel insulin-like growth factor binding protein-like protein. The novel nucleic acid of 1800 nucleotides, (192586956, SEQ ID NO: 103) encoding a novel insulin-like growth factor binding protein-like protein is shown in Table 2E. The start and stop codons are in bold. Since the start and stop codons are not traditional initiation and termination codons, MOL2c could be a partial reading frame that could extend in the 5' and/or 3 ' directions.

Table 2E. MOL2c Nucleotide Sequence (SEQ ID NO:103)

GGATCCGATTCTGACATATCGGTGGAAATTTGCAATGTGTGTTCCTGCGTGTCAGTTGAGAATGTGCTCTATGTCAA CTGTGAGAAGGTTTCAGTCTACAGACCAAATCAGCTGAAACCACCTTGGTCTAATTTTTATCACCTCAATTTCCAAA ATAATTTTTTAAATATTCTGTATCCAAATACATTCTTGAATTTTTCAGATGCAGTCTCCCTGCATCTGGGGAATAAT AAACTGCAGAACATTGAGGGAGGAGCCTTTCTTGGGCTCAGTACATTAAAGCAGTTGCACTTGAACAACAATGAATT AAAGATTCTCCGAGCTGACACTTTCCTTGGCATAGAGAACTTGGAGTATCTCCAGGCTGACTACAATTTAATCAAGT ATATTGAACGAGGAGCCTTCAATAAGCTCCACAAACTGAAAGTTCTCATTCTTAATGACAATCTGATTTCATTCCTT CCTGATAATATTTTCCGATTCGCATCTTTGACCCATCTGGATATACGAGGGAACAGAATCCAGAAGCTCCCTTATAT CGGGGTTCTGGAACACATTGGTCGTGTCGTTGAATTGCAACTGGAAGATAACCCTTGGAACTGTAGCTGTGATTTAT GCCCTTAAAAGCTTGGCTGGAGAACATGCCATATAACATTTACATAGGAGAAGCTATCTGTGAAACTCCCAGTGAC TATATGGAAGGCTTTTAAAAGAAACCAACAAACAAGAGCTATGTCCCATGGGCACCGGCAGTGATTTTGACGTGCG CATCCTGCCTCCATCTCAGCTGGAAAATGGCTACACCACTCCCAATGGTCACACTACCCAAACATCTTTACACAGAT AGTAACTAAACCACCAAAAACAACAAATCCTTCCAAGATCTCTGGAATCGTTGCAGGTAAAGCCCTCTCCAACCGC AATCTCAGTCAGATTGTGTCTTACCAAACAAGGGTGCCTCCTCTAACACCTTGCCCGGCACCTTGCTTCTGCAAAAC ACACCCTTCAGATTTGGGACTAAGTGTGAACTGCCAAGAGAAAAATATACAGTCTATGTCTGAACTGATACCGAAAC CTTTAAATGCGAAGAAGCTGCACGTCAATGGCAATAGCATCAAGGATGTGGACGTATCAGACTTCACTGACTTTGAA GGACTGGATTTGCTTCATTTAGGCAGCAATCAAATTACAGTGATTAAGGGAGACGTATTTCACAATCTCACTAATTT ACGCAGGCTATATCTCAATGGCAATCAAATTGAGAGACTCTATCCTGAAATATTTTCAGGTCTTCATAACCTGCAGT ATCTGTATTTGGAATACAATTTGATTAAGGAAATCTCAGCAGGCACCTTTGACTCCATGCCAAATTTGCAGTTACTG TACTTAAGCAATAATCTCCTAAAGAGCCTGCCTGTTTACATCTTTTCCGGAGCACCCTTAGCTAGACTGAACCTGAG GAACAACAAATTCATGTACCTGCCTGTCAGTGGGGTCCTTGATCAGTTGCAATCTCTTACACAGATTGACTTGGAGG GCAGCCCATGGGACTATACTTGTGACTTGGTGGCATTAAAGCTGTGGGTGGAGAAGTTGAGCGACGGGATTGTTGTG AAGAACTGAAATGTGAGACGCCTGTTCAGTTTACCAACATTGAACTGAAGTCCCTCAAAAATGAAATCTTATGTCC CAAACTTTTAAATAAGCCGTCTGCACCATTCACAAGCCCTGCACCTGCCATTACATTCACCACTCCTTTGGGTCCCA TTCGAAGTCCTCCTGGTGGGCCACTCGAG An open reading frame (ORF) for MOL2c was identified from nucleotides 1 to 1800. The disclosed MOL2c polypeptide (SEQ ID NO: 104) encoded by SEQ ID NO: 103 has 600 amino acid residues and is presented using the one-letter code in Table 2F.

Table 2F. Encoded MOL2c protein sequence (SEQ ID NO:104).

GSDSDISVEICNVCSCVSVENVLYVNCEKVSVYRPNQLKPP SNFYHLNFQNNFLNILYPNTFLNFSHAVSLHLGNN KLQNIEGGAFLGLSTLKQLHLNNNELKILRADTFLGIENLEYLQADYNLIKYIERGAFNKLHKLKVLILNDNLISFL PDNIFRFASLTHLDIRGNRIQ LPYIGVLEHIGRWELQLEDNPWNCSCDLLPLKA LENMPYNIYIGEAICETPSD LYGRLLKETNKQELCPMGTGSDFDVRILPPSQLENGYTTPNGHTTQTSLHRLVTKPPKTTNPSKISGIVAGKALSNR NLSQIVSYQTRVPPLTPCPAPCFCKTHPSDLGLSVNCQEKNIQSMSELIPKPLNAKKLHVNGNSIKDVDVSDFTDFE GLDLLHLGSNQITVIKGDVFHNLTNLRRLYLNGNQIERLYPEIFSGLHNLQYLYLEYNLIKEISAGTFDS PNLQLL YLSNNLLKSLPVYIFSGAPLARLNLRNNKFMYLPVSGVLDQLQSLTQIDLEGSP DYTCDLVAL L VEKLSDGIW KELKCETPVQFTNIELKSLKNEILCPKLLNKPSAPFTSPAPAITFTTPLGPIRSPPGGPLE

Table 2G shows a ClustalW alignment ofthe MOL2 variants.

Table 2G. ClustalW alignment of MOL2 variants

70 30 90 100 110 120

SVEICSWCSCVSVENVLYV CEKVSVYRPWQLKPP SIJFYHL FQNNFLNILYPNTFL]: .SVEIClWCSCVSVENVLYVNCEKVSVYRPNQLKPP SNFYHLNFQNNFLNILYPNTFLl ^VEICNVCSCVSVENVLYVNCEKVSVYRPNQL PP SNFYHLNFQNNFLNILYPNTFLl

130 140 150 160 170 180

MOL2a IffiM-^efMAlϊ-lTeπi-φϊ lfttϊnff-inMMMΪHAM WWtft !V4i MOL2b SHAVSLHLGNNIOiQNIEGGAFLGLSALKQLHLlTONELKILRADTFgGIENLEYLQAD^'! MOL2c SimVSLHLGNN LONIEGGAFLGLSBLKOLHLNii ELKILRADTFLGIENLEYLOADYl

190 200 210 220 230 240

MOL2a jIKYIERGAFNKLHKLKV ILN MOL2b JIKYIERGAFN LH LKVLILNDNLISFLPDMIFRFASLTHLDIRGNRIQKLPYIGVL. MOL2C JI YIERGAFNKLHKLKVLILNDNLISFLPDMIFRFASLTHLDIRGNRIQ LPYIGVLE:

250 260 270 280 290 300

;LQLEDNP N 30C

LGRWELQLEDNPW CSCDLLPLKA LENMPYNIYIGEAICETPSDLYGRLLKETNKQE. GRVnELQLEDNPW CSCDLLPLKA LENMPY IYIGEAICETPSDLYGRLLKETNKQE:

310 320 330 340 350 360

TGSDFDVRILPPSQLENGYTTP GHTTQTSLHRLVTKPPKTTNPSKISGIVAGI :PMGTGSDFDVRILPPSQLENGYTTPNGHTTQTSLHRLV PP TTNPSKISGIVAGB !PMGTGSDFDVRILPPSQLENGYTTPNGHTTQTSLHRLVTKPPKTTNPS ISGIVAGI

370 380 390 400 410 420

NLSQIVSYQTRVPPLTPCPAPCFCKTHPSDLGLSVNCQEKNIQSMSELIP PLNAK 3NRNLSQIVSYQTRVPPLTPCPAPCFCKTHPSDLGLSVNCQEKNIQSMSELIP PLNAK 3NRNLSQIVSYQTRVPPLTPCPAPCFCKTHPSDLGLSVNCQEKNIQSMSELIPKPLNAK

430 440 450 460 470 480

MOL2a LHVNGNSIKDVDVSDFTDFEGLDLLHLGSNQITVI!___G_.D-V-FIHNLTNLRRLYLNGNQIERL 480 MOL2b njwrøW2"M____I______I___i______l__^^ KiWΪMM 425 MOL2C n?ϊwιewS-κϊπTO*fit»)a-«»)MMe)ni)nn:ι«ιewiv;ι»>ι<w<«: e)titia:iι W^. .^W 425

490 500 510 520 530 540

M0L2 EIFSGLHNLQYLYLEYNLIKEI, M0L2b EIFSGLHI^QYLYLEYNLI EISAGTFDSMPNLQLLYL NNLL SLPVYIFSGAPLAR] M0L2c EIFSGLHlJLQYLYLEYNLIKEISAGTFDSMPNLQLLYLiNNLL SLPVYIFSGAPLARl

550 560 570 580 590 S00

M0L2 ILRRØJKFMYLPVSGVLDQLQSLTQIDLEGNP DCTCDLVALKLWVEKLSDGIVV ELKC M0L2b ^"LRNNKFMYLPVSGVLDQLQSLTQIDLEGNPWDCTCDLVAL LWV@KLSDGIWKELKΑ M0L2c LRNNKFMYLPVSGVLDQLQSLTQIDLEGΘP DHTCDLVAL LWVEKLSDGIWKELKC

670 680 690 700 710 720

M0L2a LSI W ILTVFVAFCLLVFVLRRNK PTVKHEGLGNPDCGSMQLQLRKHDHKTNKKDGL 720 M0L2b , 600 M0L2C , soo

730 740 750 760 770 780

MOL2a STEAFIPQTIEQMSKSHTCGLKESETGFMFSDPPGQKVVMRNVADKEKDLLHVDTRKRLS 780 MOL2b , , 600 MOL2C 600

790 300 810 820 830 340

MOL2a TIDELDELFPSRDSNVFIQNFLESKKEYNSIGVSGFEIRYPEKQPDKKSKKSLIGGNHSK 840 M0L2b , 600 MOL2c , , 600

850 860 870

MOL2a IWEQRKSEYFELKA LQSSPDYLQVLEEQTALN I 876 MOL2b 600 MOL2C 600

Other BLAST results including the sequences used for ClustalW analysis are presented in Table 2H

This information is presented graphically in the multiple sequence alignment given in Table 2I(with MOL2a being shown on line 1) as a ClustalW analysis comparing MOL2a with related protein sequences.

Table 21 Information for the ClustalW proteins:

1) Novel MOL2a (SEQ ID NO: 6)

2) gi| 6691962|emb|CAB65788.l] (AL080239) insulin-like growth factor binding protein, acid labile subunit)) [Homo sapiens] (SEQ ID NO:30)

3) gi| 14424224 |sp|θ9499l| Y918_HUMAN HYPOTHETICAL PROTEIN KIAA0918 [Homo Sapiens] (SEQ ID NO:31)

4) gi|ll877257|emb|CAC18888.l| (AL109653) bG115 3.1 (novel protein) [Homo sapiens] (SEQ ID NO: 32)

5) gi 112733935 |re |XP_011654.11 KIAA0848 protein [Homo sapiens] (SEQ ID NO: 33)

6) gi|7662336|ref |NP_055741.l| KIAA0848 protein [Homo sapiens] (SEQ ID NO: 34)

Table 2Jlists the domain description from DOMAIN analysis results against MOL2a. The region from amino acid residue 252 through 302 (SEQ ID NO:6) most probably (E = le-⁶) contains a "leucine rich repeat C-terminal" domain, aligned here in Table 2J This indicates that the MOL2a sequence has properties similar to those of other proteins known to contain this domain.

MOL2a

Smart I smart00082

ID N0:89)

Chromosomal information

The Insulin-like growth factor binding protein-like protein disclosed in this invention maps to chromosome Xq26.3-28.

Tissue expression

MOL2 is expressed in at least the following tissues: adrenal gland, lymphatic tissues, and heart. Other tissues known to express insulin-like growth factor binding proteins are likely. Uses of the Compositions of the Invention

The expression pattern, map location and protein similarity information for MOL2 suggest that this a Insulin-like growth factor binding protein-like protein may function as a member ofthe Insulin-like growth factor binding protein-like protein family. Therefore, the MOL2 nucleic acids and proteins are useful in potential therapeutic applications implicated, for example but not limited to, in various pathologies /disorders as described below and/or other pathologies/disorders. Potential therapeutic uses for MOL2 are, for example but not limited to, the following: (i) Protein therapeutic, (ii) small molecule drug target, (iii) antibody target (therapeutic, diagnostic, drug targeting/cytotoxic antibody), (iv) diagnostic and/or prognostic marker, (v) gene therapy (gene delivery/gene ablation), (vi) research tools, and (vii) tissue regeneration in vitro and in vivo (regeneration for all these tissues and cell types composing these tissues and cell types derived from these tissues). The MOL2 nucleic acids and proteins are useful in potential therapeutic applications implicated in various diseases and disorders described below and/or other pathologies and disorders. For example, but not limited to, a cDNA encoding the a Insulin-like growth factor binding protein-like protein may be useful in gene therapy, and the a Insulin-like growth factor binding protein-like protein may be useful when administered to a subject in need thereof. By way of nonlimiting example, the compositions ofthe present invention will have efficacy for treatment of patients suffering from cancer, diabetes, cardiomyopathy, atherosclerosis, hypertension, congenital heart defects, aortic stenosis, atrial septal defect (ASD), atrioventricular (A-V) canal defect, ductus arteriosus, pulmonary stenosis, subaortic stenosis, ventricular septal defect (VSD), valve diseases, tuberous sclerosis, scleroderma, obesity, transplantation, hemophilia, hypercoagulation, idiopathic thrombocytopenic purpura, autoimmume disease, allergies, immunodeficiencies, graft versus host disease (GVHD), lymphaedema, adrenoleukodystrophy, and/or congenital adrenal hyperplasia. MOL2, or fragments thereof, may further be useful in diagnostic applications, wherein the presence or amount ofthe nucleic acid or the protein are to be assessed. These materials are further useful in the generation of antibodies that bind immuno-specifically to the novel MOL2 substances for use in therapeutic or diagnostic methods. These antibodies may be generated according to methods known in the art, using prediction from hydrophobicity charts, as described in the "Anti-MOLX Antibodies" section below. The disclosed MOL2 protein has multiple hydrophilic regions, each of which can be used as an immunogen. In one embodiment, a contemplated MOL2 epitope is from about amino acids 75 to 120. In another embodiment, a MOL2 epitope is from about amino acids 180 to 200. In additional embodiments, MOL2 epitopes are from about amino acids 280 to 380, 400 to 450, 475 to 500, and from about amino acids 680 to 850. These novel proteins can also be used to develop assay systems for functional analysis.

MOL3

MOL3a

An additional protein ofthe invention, referred to herein as MOL3a, is a human Semaphorin B-like protein. The novel nucleic acid of 2271 nucleotides (SC85516573_EXT, SEQ ID NO:7) encoding a novel olfactory receptor-like protein is shown in Table 3A. An open reading frame (ORF) was identified beginning with an ATG initiation codon at nucleotides 1-3 and ending with a TAA codon at nucleotides 2269- 2271. The nucleotide sequence is presented in Table 3A with the start and stop codons are in bold letters.

Table 3A. MOL3a Nucleotide Sequence (SEQ ID NO:7)

ATGGCCCTCCCAGCCCTGGGCCTGGACCCCTGGAGCCTCCTGGGCCTTTTCCTCTTCCAACTGCTTC AGCTGCTGCTGCCGACGACGACCGCGGGGGGAGGCGGGCAGGGGCCCATGCCCAGGGTCAGATACTA TGCAGGGGATGAACGTAGGGCACTTAGCTTCTTCCACCAGAAGGGCCTCCAGGATTTTGACACTCTG CTCCTGAGTGGTGATGGAAATACTCTCTACGTGGGGGCTCGAGAAGCCATTCTGGCCTTGGATATCC AGGATCCAGGGGTCCCCAGGCTAAAGAACATGATACCGTGGCCAGCCAGTGACAGAAAAAAGAGTGA ATGTGCCTTTAAGAAGAAGAGCAATGAGACACAGTGTTTCAACTTCATCCGTGTCCTGGTTTCTTAC AATGTCACCCATCTCTACACCTGCGGCACCTTCGCCTTCAGCCCTGCTTGTACCTTCATTGAACTTC AAGATTCCTACCTGTTGCCCATCTCGGAGGACAAGGTCATGGAGGGAAAAGGCCAAAGCCCCTTTGA CCCCGCTCACAAGCATACGGCTGTCTTGGTGGATGGGATGCTCTATTCTGGTACTATGAACAACTTC CTGGGCAGTGAGCCCATCCTGATGCGCACACTGGGATCCCAGCCTGTCCTCAAGACCGACAACTTCC TCCGCTGGCTGCATCATGACGCCTCCTTTGTGGCAGCCATCCCTTCGACCCAGGTCGTCTACTTCTT CTTCGAGGAGACAGCCAGCGAGTTTGACTTCTTTGAGAGGCTCCACACATCGCGGGTGGCTAGAGTC TGCAAGAATGACGTGGGCGGCGAAAAGCTGCTGCAGAAGAAGTGGACCACCTTCCTGAAGGCCCAGC TGCTCTGCACCCAGCCGGGGCAGCTGCCCTTCAACGTCATCCGCCACGCGGTCCTGCTCCCCGCCGA TTCTCCCACAGCTCCCCACATCTACGCAGTCTTCACCTCCCAGTGGCAGGTTGGCGGGACCAGGAGC TCTGCGGTTTGTGCCTTCTCTCTCTTGGACATTGAACGTGTCTTTAAGGGGAAATACAAAGAGTTGA ACAAAGAAACTTCACGCTGGACTACTTATAGGGGCCCTGAGACCAACCCCCGGCCAGGCAGTTGCTC AGTGGGCCCCTCCTCTGATAAGGCCCTGACCTTCATGAAGGACCATTTCCTGATGGATGAGCAAGTG GTGGGGACGCCCCTGCTGGTGAAATCTGGCGTGGAGTATACACGGCTTGCAGTGGAGACAGCCCAGG GCCTTGATGGGCACAGCCATCTTGTCATGTACCTGGGAACCAGTACAGGGTCGCTCCACAAGGCTGT GGTAAGTGGGGACAGCAGTGCTCATCTGGTGGAAGAGATTCAGCTGTTCCCTGACCCTGAACCTGTT CGCAACCTGCAGCTGGCCCCCACCCAGGGTGCAGTGTTTGTAGGCTTCTCAGGAGGTGTCTGGAGGG TGCCCCGAGCCAACTGTAGTGTCTATGAGAGCTGTGTGGACTGTGTCCTTGCCCGGGACCCCCACTG TGCCTGGGACCCTGAGTCCCGACTCTGCTCTCTTAGGAACTCCTGGAAGCAGGACATGGAGCGGGGG AACCCAGAGTGGGCATGTGCCAGTGGCCCCATGAGCAGGAGCCTTCGGCCTCAGAGCCGCCCGCAAA TCGTTAAAGAAGTCCTGGCTGTCCCCAACTCCATCCTGGAGCTCCCCTGCCCCCACCTGTCAGCCTT GGCCTCTTATTATTGGAGTCATGGCCCAGCAGCAGTCCCAGAAGCCTCTTCCACTGTCTACAATGGC TCCCTCTTGCTGATAGTGCAGGATGGAGTTGGGGGTCTCTACCAGTGCTGGGCAACTGAGAATGGCT TTTCATACCCTGTGATCTCCTACTGGGTGGACAGCCAGGACCAGACCCTGGCCCTGGATCCTGAACT GGCAGGCATCCCCCGGGAGCATGTGAAGGTCCCGTTGACCAGGGTCAGTGGTGGGGCCGCCCTGGCT GCCCAGCAGTCCTACTGGCCCCACTTTGTCACTGTCACTGTCCTCTTTGCCTTAGTGCTTTCAGGAG CCCTCATCATCCTCGTGGCCTCCCCATTGAGAGCACTCCGGGCTCGGGGCAAGGTTCAGGGCTGTGA GACCCTGCGCCCTGGGGAGAAGGCCCCGTTAAGCAGAGAGCAACACCTCCAGTCTCCCAAGGAATGC AGGACCTCTGCCAGTGATGTGGACGCTGACAACAACTGCCTAGGCACTGAGGTAGCTTAA

The disclosed MOL3a polypeptide (SEQ ID NO: 8) encoded by SEQ ID NO:7 has 756 amino acid residues, and is presented using the one-letter code in Table 3B. The MOL3a protein was analyzed for signal peptide prediction and cellular localization. SignalP results predict that MOL3a is cleaved between position 31 and 32 (TTA-GG) of SEQ ID NO: 8. Psort and Hydropathy profiles also predict that MOL3a is likely to be localized at the plasma membrane (certainty of 0.7300).

Table 3B. Encoded MOL3a protein sequence (SEQ ID NO:8).

MALPALGLDPWSLLGLFLFQLLQLLLPTTTAGGGGQGPMPRVRYYAGDERRALSFFHQKGLQDFDTLLLSGDGNT LYVGAREAILALDIQDPGVPRL NMIPWPASDRKKSECAFK KSWETQCFNFIRVLVSYNVTHLYTCGTFAFSPA CTFIELQDSYLLPISEDKVMEGKGQSPFDPAHKHTAVLVDGMLYSGTMN FLGSEPILMRTLGSQPVLKTDNFLR WLHHDASFVAAIPSTQWYFFFEETASEFDFFERLHTSRVARVCKNDVGGEKLLQKK TTFLKAQLLCTQPGQLP FNVIRHAVLLPADSPTAPHIYAVFTSQWQVGGTRSSAVCAFSLLDIERVFKGKYKELNKETSRWTTYRGPETNPR PGSCSVGPSSDKALTFMKDHFLMDEQWGTPLLVKSGVEYTRLAVETAQGLDGHSHLVMYLGTSTGSLHKAWSG DSSAHLVEEIQLFPDPEPVRNLQLAPTQGAVFVGFSGGVWRVPRANCSVYESCVDCVLARDPHCA DPESRLCSL RNSWKQDMERGNPEWACASGPMSRSLRPQSRPQIVKEVLAVPNSILELPCPHLSALASYYWSHGPAAVPEASSTV YNGSLLLIVQDGVGGLYQCWATENGFSYPVISYWVDSQDQTLALDPELAGIPREHVKVPLTRVSGGAALAAQQSY PHFVTVTVLFALVLSGALIILVASPLRALRARGKVQGCETLRPGEKAPLSREQHLQSPKECRTSASDVDADNNC LGTEVA

The MOL3a nucleic acid sequence has 1398/1672 (83%) identical to a mouse Semaphorin B mRNA (GENBANK-ID: X85991 ).

The full amino acid sequence of MOL3a was found to have 628 of 760 (82%) identical to, and 674 of 760 residues (88%) homologous with, the 760 amino acid residue Semaphorin B protein from mouse (ptnr: SWISSNEW-ACC:Q62178).

MOL3a expression in different tissues was examined through TaqMan as described below in Example 1.

MOL3a also has high homology to the proteins disclosed in the BLASTP searches ofthe proprietary PATP database shown in Table 3C.

Tissue Localization

MOL3a is expressed in at least the following tissues: Pituitary Gland, Thalamus Chromosomal Localization MOL3a maps to chromosome 1 .

MOL3b

In the present invention, the target sequence identified previously, MOL3a, was subjected to the exon linking process to confirm the sequence. PCR primers were designed by starting at the most upstream sequence available, for the forward primer, and at the most downstream sequence available for the reverse primer. In each case, the sequence was examined, walking inward from the respective termini toward the coding sequence, until a suitable sequence that is either unique or highly selective was encountered, or, in the case ofthe reverse primer, until the stop codon was reached. Such primers were designed based on in silico predictions for the full length cDNA, part (one or more exons) ofthe DNA or protein sequence ofthe target sequence, or by translated homology ofthe predicted exons to closely related human sequences sequences from other species. These primers were then employed in PCR amplification based on the following pool of human cDNAs: adrenal gland, bone marrow, brain - amygdala, brain - cerebellum, brain - hippocampus, brain - substantia nigra, brain - thalamus, brain -whole, fetal brain, fetal kidney, fetal liver, fetal lung, heart, kidney, lymphoma - Raji, mammary gland, pancreas, pituitary gland, placenta, prostate, salivary gland, skeletal muscle, small intestine, spinal cord, spleen, stomach, testis, thyroid, trachea, uterus. Usually the resulting amplicons were gel purified, cloned and sequenced to high redundancy. The resulting sequences from all clones were assembled with themselves, with other fragments in CuraGen Corporation's database and with public ESTs. Fragments and ESTs were included as components for an assembly when the extent of their identity with another component ofthe assembly was at least 95% over 50 bp. In addition, sequence traces were evaluated manually and edited for corrections if appropriate. These procedures provide the sequence reported below, which is designated MOL3b, or alternatively Accession Number CG53027-02. This is a spliced variant ofthe previously identified sequence (Accession Number SC85516573_EXT) at amino acids 293-329.

A protein ofthe invention, referred to herein as MOL3b, is a human Semaphorin B-like protein. The novel nucleic acid of 2281 nucleotides (CG53027-02, SEQ ID NO:9) encoding a Semaphorin B-like protein is shown in Table 3D. An open reading frame (ORF) was identified beginning with a non-initiating codon for the mature protein at nucleotides 2-4 and ending with non-stop codon at nucleotides 2264-2266. The open reading frame may be extendable in both the 5' and 3' directions because ofthe lack of traditional start and stop codons. The nucleotide sequence is presented in Table 3D with the start and stop codons in bold letters and the 5' and 3' untranslated regions underlined.

Table 3D. MOL3b Nucleotide Sequence (SEQ ID NO:9)

GCCTGTGCCTAGAGTTTAAGCTACCTCAGTGCCTAGGCAGTTGTTGTCAGCGTCCACATCACTGGCAGAGGTCCT GCATTCCTTGGGAGACTGGAGGTGTTGCTCTCTGCTTAACGGGGCCTTCTCCCCAGGGCGCAGGGTCTCACAGCC CTGAACCTTGCCCCGAGCCCGGAGTGCTCTCAATGGGGAGGCCACGAGGATGATGAGGGCTCCTGAAAGCACTAA GGCAAAGAGGACAGTGACAGTGACAAAGTGGGGCCAGTAGGACTGCTGGGCAGCCAGGGCGGCCCCACCACTGAC CCTGGTCAACGGGACCTTCACATGCTCCCGGGGGATGCCTGCCAGTTCAGGATCCAGGGCCAGGGTCTGGTCCTG GCTGTCCACCCAGTAGGAGATCACAGGGTATGAAAAGCCATTCTCAGTTGCCCAGCACTGGTAGAGACCCCCAAC TCCATCCTGCACTATCAGCAAGAGGGAGCCATTGTAGACAGTGGAAGAGGCTTCTGGGACTGCTGCTGGGCCATG ACTCCAATAATAAGAGGCCAAGGCTGACAGGTGGGGGCAGGGGAGCTCCAGGATGGAGTTGGGGACAGCCAGGAC TTCTTTAATGATTTGCGGGCGGCTCTGAGGCCGAAGGCTCCTGCTCATGGGGCCACTGGCACATGCCCACTCTGG GTTCCCCCGCTCCATGTCCTGCTTCCAGGAGTTCAGGTTGGGGGCAGACAGGAGGCAACAGGTTCGGGACTCAGG GTCCCAGGCACAGTGGGGGTCCCGGGCAAGGACACAGTCCACACAGCTCTCATAGACACTACAGTTGGCTCGGGG CACCCTCCAGACACCTCCTGAGAAGCCTACAAACACTGCACCCTGGGTGGGGGCCAGCTGCAGGTTGCGAACAGG TTCAGGGTCAGGGAACAGCTGAATCTCTTCCACCAGATGAGCACTGCTGTCCCCACTTACCACAGCCTTGTGGAG CGACCCTGTGGTGGTTCCCAGGTACATGACAAGATGGCTGTGCCCATCAAGGCCCTGGGCTGTCTCCACTGCAAG CCGTGTATACTCCACGCCAGATTTCACCAGCAGGGGCGTCCCCACCACTTGCTCATCCATCAGGAAATGGTCCTT CATGAAGGTCAGGGCCTTATCAGAGGAGGGGCCCACTGAGCAACTGCCTGGCCGGGGGTTGGTCTCAGGGCCCCT ATAAGTAGTCCAGCGTGAAGTTTCTTTGTTCAACTCTTTGTATTTCCCCTTAAAGACACGTTCAATGTCCAAGAG AGAGAAGGCACAAACCGCAGAGCTCCTGGTCCCGCCAACCTGCCACTGGGAGGTGAAGACTGCGTAGATGTGGGG AGCTGTGGGAGAATCGGCGGGGAGCAGGACCGCGTGGCGGATGACGTTGAAGGGCAGCTGCCCCGGCTGGGTGCA GAGCAGCTGGGCCTTCAGGAAGGTGGTCCACTTCTTCTGCAGCAGCTTTTCGCCGCCCACGTCATTCTTGCAGAC TCTAGCCACCCGCGATGTGTGGAGCCTCTCAAAGAAGTCAAACTCGCTGGCTGTCTCCTCGAAGAAGAAGTAGAC GACCTGGGTCGAAGGGATGGCTGCCACAAAGGAGGCGTCATGATGCAGCCAGCGGAGGAAGTTGTCGGTCTTGAG GACAGGCTGGGATCCCAGTGTGCGCATCAGGATGGGCTCACTGCCCAGGAAGTTGTTCATAGTACCAGAATAGAG CATCCCATCCACCAAGACAGCCGTATGCTTGTGAGCGGGGTCAAAGGGGCTTTGGCCTTTTCCCTCCATGACCTT GTCCTCCGAGATGGGCAACAGGTAGGAATCTTGAAGTTCAATGAAGGTACAAGCAGGGCTGAAGGCGAAGGTGCC GCAGGTGTAGAGATGGGTGACATTGTAAGAAACCAGGACACGGATGAAGTTGAAACACTGTGTCTCATTGCTCTT CTTCTTAAAGGCACATTCACTCTTTTTTCTGTCACTGGCTGGCCACGGTATCATGTTCTTTAGCCTGGGGACCCC TGGATCCTGGATATCCAAGGCCAGAATGGCTTCTCGAGCCCCCACGTAGAGAGTATTTCCATCACCACTCAGGAG CAGAGTGTCAAAATCCTGGAGGCCCTTCTGGTGGAAGAAGCTAAGTGCCCTACGTTCATCCCCTGCATAGTATCT GACCCTGGGCATGGGCCCCTGCCCGCCTCCCCCCGCGGTCGTCGTCGGCAGCAGCAGCTGAAGCAGTTGGAAGAG GAAAAGGCCCAGGAGGCTCCAGGGGTCCAGG

The disclosed MOL3b polypeptide (SEQ ID NO: 10) encoded by SEQ ID NO:9 has

754 amino acid residues, and is presented using the one-letter code in Table 3E. The MOL3b protein was analyzed for signal peptide prediction and cellular localization. SignalP results predict that MOL3b is cleaved between position 24 and 25 (TTA-GG) of SEQ ID NO: 10. Psort and Hydropathy profiles also predict that MOL3b is likely to be localized at the plasma membrane (certainty of 0.7300).

Table 3E. Encoded MOL3b protein sequence (SEQ TD NO:10).

LDP SLLGLFLFQLLQLLLPTTTAGGGGQGPMPRVRYYAGDERRALSFFHQKGLQDFDTLLLSGDGNTLYVGARE AILALDIQDPGVPRLKNMIPWPASDRKKSECAFKKKSNETQCFNFIRVLVSYNVTHLYTCGTFAFSPACTFIELQ DSYLLPISEDKVMEGKGQSPFDPAHKHTAVLVDGMLYSGTMNNFLGSEPIL RTLGSQPVLKTDNFLR LHHDAS FVAAIPSTQVVYFFFEETASEFDFFERLHTSRVARVC NDVGGEKLLQKK TTFLKAQLLCTQPGQLPFNVIRHA VLLPADSPTAPHIYAVFTSQ QVGGTRSSAVCAFSLLDIERVFKGKYKELNKETSR TTYRGPETNPRPGSCSVG PSSDKALTFMKDHFLMDEQWGTPLLVKSGVEYTRLAVETAQGLDGHSHLVMYLGTTTGSLHKAWSGDSSAHLV EEIQLFPDPEPVRNLQLAPTQGAVFVGFSGGVWRVPRANCSVYESCVDCVLARDPHCAWDPESRTCCLLSAPNLN SWKQDMERGNPEWACASGPMSRSLRPQSRPQIIKEVLAVPNSILELPCPHLSALASYYWSHGPAAVPEASSTVYN GSLLLIVQDGVGGLYQCWATENGFSYPVISY VDSQDQTLALDPELAGIPREHVKVPLTRVSGGAALAAQQSY P HFVTVTVLFALVLSGALIILVASPLRALRARGKVQGCETLRPGEKAPLSREQHLQSPKECRTSASDVDADNNCLG TEVA

The MOL3b nucleic acid sequence has 1910 of 2279 bases (83%>) identical to a gb:GENBANK-ID:MMRNASEMB|acc:X85991.1 mRNA from Mus musculus (M.muscuhis mRNA for semaphorin B).

The full amino acid sequence ofthe protein ofthe invention was found to have 722 of 755 amino acid residues (95%) identical to, and 723 of 755 amino acid residues (95%) similar to, the 762 amino acid residue ptnr:TREMBLNEW-ACC:BAB20087 protein from Homo sapiens (Human) (SEMB).

The presence of identifiable domains in the protein disclosed herein was determined by searches versus domain databases such as Pfam, PROSITE, ProDom, Blocks or Prints and then identified by the Interpro domain accession number. Significant domains are summarized in Table 3F.

Table 3F Domain search for MOL3b

HM ER is freely distributed under the GNU General Public License (GPL) .

HMM file: pfamHMMs

Sequence file :

/data4/genetools/ spytek35060Cg53027_01ProteinFasta.txt

Query: CG53027_01

Scores for sequence family classi ication (score includes all domains) : Model Description Score E-value N

Sema Sema domain 618.4 4.2e-182 1

Plexin_repeat Plexin repeat 22.0 0.013 1 integrin_B Integrins, beta chain 6.5 0.063 1

Parsed for domains :

Model Domain seq-f seq-t hmm-f hmm-t score E-value Sema 1/1 57 471 1 490 [] 618 . 4 4 . 2e- 182 integrin_B 1/1 495 509 1 14 [ . 6 . 5 0 . 063

Plexin_repeat 1/1 489 555 1 67 [] 22 . 0 0 . 013

Tissue Localization

MOL3b is expressed in at least the following tissues: thalamus and Pituitary Gland. Expression information was derived from the tissue sources ofthe sequences that were included in the derivation ofthe sequence of MOL3b. Chromosomal Localization OL3b maps to chromosome 1. This assignment was made using mapping information associated with genomic clones, public genes and ESTs sharing sequence identity with the disclosed sequence and CuraGen Corporation's Electronic Northern bioinformatic tool.

The disclosed MOL3a protein (SEQ ID NO:8) also has good identity with a number of other proteins, as shown in Table 3G.

This information is presented graphically in the multiple sequence alignment given in Table 3H (with MOL3a being shown on line 1 and MOL3b on line 2) as a ClustalW analysis comparing MOL3 with related protein sequences.

Table 3H. Information for the ClustalW proteins:

1) MOL3a (SEQ ID NO : 8 )

2) MOL3b (SEQ ID NO: 10)

3) gi| 12248382 |dbj |BAB20087.l| (AB029394) SEMB [Homo sapiens] (SEQ ID NO : 35 )

4) gi| 7305469|ref |NP_038686. l| sema domain, immunoglobulin domain (Ig) , transmembrane domain (TM) and short cytoplasmic domain, (semaphorin) 4A [Mus musculus] (SEQ ID NO : 36 )

5) gi| 1164129l|ref |NP_071762.l] hypothetical protein FLJ12287 similar to semaphorins [Homo sapiens] (SEQ ID NO: 37)

6) gi] 12698035|dbj ]BAB21836.l| (AB051532) KIAA1745 protein [Homo sapiens] (SEQ ID NO: 38)

7) gi|8134698|sp|Q62179|SM4B_MOUSE SEMAPHORIN 4B (SEMAPHORIN C) (SEMA C) (SEQ ID NO:39)

gi|l2698035| ^^^HRg gEG^SSvSTMKg Q^SsgL^3' ® ^QQ giJ8134698| S^^HR§ §EG^IgV§TMN§VQK gD ^^V§ ^QQ

450 460 470 480

■ - ■ ■ I - -

M0L3b Si røi lii^HWitipl^M^®!

610 620 630

M0L3a

M0L3b

Table 31 lists the domain description from DOMAIN analysis results against MOL3. The region from amino acid residue 64 through 478 (SEQ ID NO:8) most probably (E = le^"121) contains a PSI, domain found in Plexins, Semaphorins and Integrins, aligned here in Table 31. Semaphorins are involved in growth cone guidance as well as other developmental processes. Plexins and integrins are involved in developmental processes. The MOLl sequence likely has properties similar to those of other proteins known to contain this domain

Table 31. Domain Analysis of MOL3 gnl | Smart ] smart00423 , PSI , domain found in Plexins , Semaphorins and Integrins

CD-Length = 431 residues , 100 .0% aligned

Score = 430 bits (1106) , Expect = le-121

10 20 30 50

MOL3_3 JDPESRLBSLR-

Smart | smart00423 _g-mCSSQGRgTSG-

60 70

MOL3_3 Nf| KWDMERgNPEWASA

Smart| smart00423 ERCDI Slfe ssS GBP (SEQ IDNO:90)

The protein similarity information, expression pattern, cellular localization, and map location for the protein and nucleic acid for MOL3 suggest that this Semaphorin B- like protein may have important structural and/or physiological functions characteristic of the Semaphorin B family. This family is involved in developmental processes including growth cone guidance. MOL3 likely plays a similar role in those developmental processes. Therefore, the MOL3 nucleic acids and proteins are useful in potential diagnostic and therapeutic applications and as a research tool. These include serving as a specific or selective nucleic acid or protein diagnostic and/or prognostic marker, wherein the presence or amount ofthe nucleic acid or the protein are to be assessed. These also include potential therapeutic applications such as the following: (i) a protein therapeutic, (ii) a small molecule drug target, (iii) an antibody target (therapeutic, diagnostic, drug targeting/cytotoxic antibody), (iv) a nucleic acid useful in gene therapy (gene delivery/gene ablation), (v) an agent promoting tissue regeneration in vitro and in vivo, and (vi) a biological defense weapon.

The MOL3 nucleic acids and proteins have applications in the diagnosis and/or treatment of various diseases and disorders. For example, the compositions ofthe present invention will have efficacy for the treatment of patients suffering from: neuronal developmental, organizational, mediated and interactive disorders and disease; endocrine dysfunctions, diabetes, obesity, growth and reproductive disorders, injury repair as well as other diseases, disorders and conditions. These materials are further useful in the generation of antibodies that bind immuno-specifically to the novel MOL3 substances for use in therapeutic or diagnostic methods. These antibodies may be generated according to methods known in the art, using prediction from hydrophobicity charts, as described in the "Anti-MOLX Antibodies" section below. The disclosed MOL3 protein has multiple hydrophilic regions, each of which can be used as an immunogen. In one embodiment, a contemplated MOL3 epitope is from about amino acids 30 to 100. In another embodiment, a MOL3 epitope is from about amino acids 1 10 to 150. In additional embodiments, MOL3 epitopes are from about amino acids 160 to 200, 210 to 230, 250 to 300, 350 to 400, 450 to 475, 500 to 575, 620 to 630, and from about amino acids 700 to 750. These novel proteins can also be used to develop assay systems for functional analysis.

MOL4

MOL4a The disclosed novel semaphorin-like protein, MOL4a (also referred to herein as SC_111750277_A), is encoded by a nucleic acid, 6408 nucleotides long (SEQ ID NO:l 1). An open reading frame was identified beginning with an ATG initiation codon at nucleotides 1400-1402 and ending with a TGA codon at nucleotides 5456-5458. Putative untranslated regions upstream from the initiation codon and downstream from the termination codon are underlined in Table 4A, and the start and stop codons are in bold letters.

Table 4A. MOL4a Nucleotide Sequence (SEQ ID NO:11).

CCTGGGACTCTGGGAGAATGGTCCAGAGCTCATTGTCCTTGTTGATAAAATGATAGATTTGGACTCAATATCCCA TGCTGCCTCTTCCAACTTGATTTTTACCCCAGACTGGGCTACCAGACTGGTATGCCCACACATGCCCGTTTCCTT TCTTTTCTTCTCTGCATCTCTGCCTTTGTGTCCAGAGCGTGTTTTCCCTTTGCAAGTTTCTCTCCATTCTGCACA TTATGAGTTTCAGCATTTCTGTTGCCCTAGAAAGTCTATCTTTGAGATCTTGCACTGTTTCTCTTTTTACAGTGT CTCATAAACTCCCTTCTTGGATTCAGAACCACCCTTTCTTTCCCATTATCCTGTCAAACTGCTTCTTGCCATGGT CCAGGGGTAGGAGGATGGCAGGCAGGAGGTGCTTCTCTGGGGCTCTTAGTGTCTCAATTCTTCTGCTTTATCTGG GTTTTCCTTTACCCAGAATTTTATTATGTAAAATGCTTCACTCAGACTTTGTTCTAATTATCCAATTTTTGGCAT ACTCTAGAAAGTCTTTTGATATTTTCCTTCCTCCAACTTATCTATTTTTATTTCATAGTTCTCTTTGGTTATCTC TTAGAATCACACTTTCCTGGTTTTAATTTTTCAAATCCTTTGTCTTTCTCACTCGTTCTTAGGTCACCTTTTTTT ACATTTTCAAATATATTTTTTGTTCAGCAGAGGGCTCCCTTCCCATCCCTCTTGCAGCCCGGGCAGCTAGGATTT GAAGCTTGCCCCTTGAATCTTTCTCTCCCGCCTTCTAGCCATCAGAAACACTAGATCACTTAAACTTGTAAACAA TCGGCCTCGCTCCTTGTGATTGCGCTAAACCTTCCGTCCTCAGCTGAGAACGCTCCACCACCTCCCCGGATCGC TCATCTCTTGGCTGCCCTCCCACTGTTCCTGATGTTATTTTACTCCCCGTATCCCCTACTCGTTCTTCACAATTC TGTAGGGTGCGTATTACTAACCCCAGTTTACAGCTGAGGAAACTGAGGCTTGGAGAGGTTCGCTCGGTATCGTAC AGTTTGCAAGGTTAACCCTAATCCGGCCAGTTCTGGCTTTCCAGCCCAGCCCAGCAGCCTAGCCTCCCTCTCTGC CGCTGCAGGTTATAACGGCTCTCCCCCGTTTTACACGAGGTCCCTTCCCCTTCAAATCCACAGGCAGGAAGATCG TTCCGAACTGACGGGGCTGGGGAATGTGGGAGTCCGGAGTGGGGTTTGGGGGAGCTTCCTCAGGCCCTGAGTGTT GGGGTGGGCAGGCCGCGCCGATGGCCCTCGGGGATGTCACATTCGAGATGGGGTGACCGAGAACGGCAAGGCGGG ATGTGGCAAACGGCGGCAAGTGCTCGGAGTCCTAGGTCTTGCCGCCGGAATGCCGGCCGGGGAAGGGGCTTCGGC CCACCGGGCTGGTCACCACACTCGGCAGGCCCGGGGCGGGAGTCGGCCGAGCAGCCGCGGGATGCAGGGCGCCCC CTCGCGCTCCTCCGCGCGCCTCGAGGCTGGCGGGTGCAGCGCCCGCCGCGGCAGGTCTGCTCCAGCCCCCTCCTC TTTTTCGCTCCCGCTCCCCTCCTTCTCTCCCTTTGCTTGCAACTCCTCCCCCACCGCCCCCTCCCTCCTTCTGCT CCCGCGGTCTCCTCCTCCCTGCTCTCTCCGAGCGCCGGGTCGGGAGCTAGTTGGAGCGCGGGGGTTGGTGCCAGA GCCCAGCTCCGCCGAGCCGGGCGGGTCGGCAGCGCATCCAGCGGCTGCTGGGAGCCCGAGCGCAGCGGGCGCGGG CCCGGGTGGGGACTGCACCGGAGCGCTGAGAGCTGGAGGCCGTTCCTGCGCGGCCGCCCCATTCCCAGACCGGCC GCCAGCCCATCTGGTTAGCTCCCGCCGCTCCGCGCCGCCCGGGAGTCGGGAGCCGCGGGGAACCGGGCACCTGCA CCCGCCTCTGGGAGTGAGTGGTTCCAGCTGGTGCCTGGCCTGTGTCTCTTGGATGCCCTGTGGCTTCAGTCCGTC TCCTGTTGCCCACCACCTCGTCCCTGGGCCGCCTGATACCCCAGCCCAACAGCTAAGGTGTGGATGGACAGTAGG GGGCTGGCTTCTCTCACTGGTCAGGGGTCTTCTCCCCTGTCTGCCTCCCGGAGCTAGGACTGCAGAGGGGCCTAT CATGGTGCTTGCAGGCCCCCTGGCTGTCTCGCTGTTGCTGCCCAGCCTCACACTGCTGGTGTCCCACCTCTCCAG CTCCCAGGATGTCTCCAGTGAGCCCAGCAGTGAGCAGCAGCTGTGCGCCCTTAGCAAGCACCCCACCGTGGCCTT TGAAGACCTGCAGCCGTGGGTCTCTAACTTCACCTACCCTGGAGCCCGGGATTTCTCCCAGCTGGCTTTGGACCC CTCCGGGAACCAGCTCATCGTGGGAGCCAGGAACTACCTCTTCAGACTCAGCCTTGCCAATGTCTCTCTTCTTCA GGCCACAGAGTGGGCCTCCAGTGAGGACACGCGCCGCTCCTGCCAAAGCAAAGGGAAGACTGAGGAGGAGTGTCA GAACTACGTGCGAGTCCTGATCGTCGCCGGCCGGAAGGTGTTCATGTGTGGAACCAATGCCTTTTCCCCCATGTG CACCAGCAGACAGGTGGGGAACCTCAGCCGGACTACTGAGAAGATCAATGGTGTGGCCCGCTGCCCCTATGACCC ACGCCACAACTCCACAGCTGTCATCTCCTCCCAGGGGGAGCTCTATGCAGCCACGGTCATCGACTTCTCAGGTCG GGACCCTGCCATCTACCGCAGCCTGGGCAGTGGGCCACCGCTTCGCACTGCCCAATATAACTCCAAGTGGCTTAA TGAGCCAAACTTCGTGGCAGCCTATGATATTGGGCTGTTTGCATACTTCTTCCTGCGGGAGAACGCAGTGGAGCA CGACTGTGGACGCACCGTGTACTCTCGCGTGGCCCGCGTGTGCAAGAATGACGTGGGGGGCCGATTCCTGCTGGA GGACACATGGACCACATTCATGAAGGCCCGGCTCAACTGCTCCCGCCCGGGCGAGGTCCCCTTCTACTATAACGA GCTGCAGAGTGCCTTCCACTTGCCAGAGCAGGACCTCATCTATGGAGTTTTCACAACCAACGTAAACAGCATCGC GGCTTCTGCTGTCTGCGCCTTCAACCTCAGTGCTATCTCCCAGGCTTTCAATGGCCCATTTCGCTACCAGGAGAA CCCCAGGGCTGCCTGGCTCCCCATAGCCAACCCCATCCCCAATTTCCAGTGTGGCACCCTGCCTGAGACCGGTCC CAACGAGAACCTGACGGAGCGCAGCCTGCAGGACGCGCAGCGCCTCTTCCTGATGAGCGAGGCCGTGCAGCCGGT GACACCCGAGCCCTGTGTCACCCAGGACAGCGTGCGCTTCTCACACCTCGTGGTGGACCTGGTGCAGGCTAAAGA CACGCTCTACCATGTACTCTACATTGGCACCGAGTCGGGCACCATCCTGAAGGCGCTGTCCACGGCGAGCCGCAG CCTCCACGGCTGCTACCTGGAGGAGCTGCACGTGCTGCCCCCCGGGCGCCGCGAGCCCCTGCGCAGCCTGCGCAT CCTGCACAGCGCCCGCGCGCTCTTCGTGGGGCTGAGAGACGGCGTCCTGCGGGTCCCACTGGAGAGGTGCGCCGC CTACCGCAGCCAGGGGGCATGCCTGGGGGCCCGGGACCCGTACTGTGGCTGGGACGGGAAGCAGCAACGTTGCAG CACACTCGAGGACAGCTCCAACATGAGCCTCTGGACCCAGAACATCACCGCCTGTCCTGTGCGGAATGTGACACG GGATGGGGGCTTCGGCCCATGGTCACCATGGCAACCATGTGAGCACTTGGATGGGGACAACTCAGGCTCTTGCCT GTGTCGAGCTCGATCCTGTGATTCCCCTCGACCCCGCTGTGGGGGCCTTGACTGCCTGGGGCCAGCCATCCACAT CGCCAACTGCTCCAGGAATGGGGCGTGGACCCCGTGGTCATCGTGGGCGCTGTGCAGCACGTCCTGTGGCATCGG CTTCCAGGTCCGCCAGCGAAGTTGCAGCAACCCTGCTCCCCGCCACGGGGGCCGCATCTGCGTGGGCAAGAGCCG GGAGGAACGGTTCTGTAATGAGAACACGCCTTGCCCGGTGCCCATCTTCTGGGCTTCCTGGGGCTCCTGGAGCAA GTGCAGCAGCAACTGTGGAGGGGGCATGCAGTCGCGGCGTCGGGCCTGCGAGAACGGCAACTCCTGCCTGGGCTG CGGCGTGGAGTTCAAGACGTGCAACCCCGAGGGCTGCCCCGAAGTGCGGCGCAACACCCCCTGGACGCCGTGGCT GCCCGTGAACGTGACGCAGGGCGGGGCACGGCAGGAGCAGCGGTTCCGCTTCACCTGCCGCGCGCCCCTTGCAGA CCCGCACGGCCTGCAGTTCGGCAGGAGAAGGACCGAGACGAGGACCTGTCCCGCGGACGGCTCCGGCTCCTGCGA CACCGACGCCCTGGTGGAGGACCTCCTGCGCAGCGGGAGCACCTCCCCGCACACGGTGAGCGGGGGCTGGGCCGC CTGGGGCCCGTGGTCGTCCTGCTCCCGGGACTGCGAGCTGGGCTTCCGCGTCCGCAAGAGAACGTGCACTAACCC GGAGCCCCGCAACGGGGGCCTGCCCTGCGTGGGCGATGCTGCCGAGTACCAGGACTGCAACCCCCAGGCTTGCCC AGTTCGGGGTGCTTGGTCCTGCTGGACCTCATGGTCTCCATGCTCAGCTTCCTGTGGTGGGGGTCACTATCAACG CACCCGTTCCTGCACCAGCCCCGCACCCTCCCCAGGTGAGGACATCTGTCTCGGGCTGCACACGGAGGAGGCACT ATGTGCCACACAGGCCTGCCCAGAAGGCTGGTCGCCCTGGTCTGAGTGGAGTAAGTGCACTGACGACGGAGCCCA GAGCCGAAGCCGGCACTGTGAGGAGCTCCTCCCAGGGTCCAGCGCCTGTGCTGGAAACAGCAGCCAGAGCCGCCC CTGCCCCTACAGCGAGATTCCCGTCATCCTGCCAGCCTCCAGCATGGAGGAGGCCACCGGCTGTGCAGGGTTCAA TCTCATCCACTTGGTGGCCACGGGCATCTCCTGCTTCTTGGGCTCTGGGCTCCTGACCCTAGCAGTGTACCTGTC TTGCCAGCACTGCCAGCGTCAGTCCCAGGAGTCCACACTGGTCCATCCTGCCACCCCCAACCATTTGCACTACAA GGGCGGAGGCACCCCGAAGAATGAAAAGTACACACCCATGGAATTCAAGACCCTGAACAAGAATAACTTGATCCC TGATGACAGAGCCAACTTCTACCCATTGCAGCAGACCAATGTGTACACGACTACTTACTACCCAAGCCCCCTGAA CAAACACAGCTTCCGGCCCGAGGCCTCACCTGGACAACGGTGCTTCCCCAACAGCTGATACCGCCGTCCTGGGGA CTTGGGCTTCTTGCCTTCATAAGGCACAGAGCAGATGGAGATGGGACAGTGGAGCCAGTTTGGTTTTCTCCCTCT GCACTAGGCCAAGAACTTGCTGCCTTGCCTGTGGGGGGTCCCATCCGGCTTCAGAGAGCTCTGGCTGGCATTGAC CATGGGGGAAAGGGCTGGTTTCAGGCTGACATATGGCCGCAGGTCCAGTTCAGCCCAGGTCTCTCATGGTTATCT TCCAACCCACTGTCACGCTGACACTATGCTGCCATGCCTGGGCTGTGGACCTACTGGGCATTTGAGGAACTGGAG AATGGAGATGGCAAGAGGGCAGGCTTTTAAGTTTGGGTTGGAGACAACTTCCTGTGGCCCCCACAAGCTGAGTCT GGCCTTCTCCAGCTGGCCCCAAAAAAGGCCTTTGCTACATCCTGATTATCTCTGAAAGTAATCAATCAAGTGGCT CCAGTAGCTCTGGATTTTCTGCCAGGGCTGGGCCATTGTGGTGCTGCCCCAGTATGACATGGGACCAAGGCCAGC GCAGGTTATCCACCTCTGCCTGGAAGTCTATACTCTACCCAGGGCATCCCTCTGGTCAGAGGCAGTGAGTACTGG GAACTGGAGGCTGACCTGTGCTTAGAAGTCCTTTAATCTGGGCTGGTACAGGCCTCAGCCTTGCCCTCAATGCAC GAAAGGTGGCCCAGGAGAGAGGATCAATGCCACAGGAGGCAGAAGTCTGGCCTCTGTGCCTCTATGGAGACTATC TTCCAGTTGCTGCTCAACAGAGTTGTTGGCTGAGACCTGCTTGGGAGTCTCTGCTGGCCCTTCATCTGTTCAGGA ACACACACACACACACACTCACACACGCACACACAATCACAATTTGCTACAGCAACAAAAAAGACATTGGGCTGT GGCATTATTAATTAAAGATGATATCCAGTCTCC The 1352 amino acid MOL4a polypeptide (SEQ ID NO: 12) encoded by SEQ ID NO:11 is presented using the one-letter amino acid code in Table 4B. The Psort profile for MOL4a predicts that this sequence has no signal peptide and is likely to be localized in the plasma membrane with a certainty of0.7900. MOL4a has a molecular weight of 145674.1 Daltons.

Table 4B. MOL4a protein sequence (SEQ ID NO:12)

MPAGEGASAHRAGHHTRQARGGSRPSSRGMQGAPSRSSARLEAGGCSARRGRSAPAPSSFSLPLPSFSPFACNSSP TAPSLLLLPRSPPPCSLRAPGRELVGARGLVPEPSSAEPGGSAAHPAAAGSPSAAGAGPGGDCTGALRAGGRSCAA APFPDRPPAHLVSSRRSAPPGSREPRGTGHLHPPLGVSGSS CLACVSWMPCGFSPSPVAHHLVPGPPDTPAQQLR CG TVGG LLSLVRGLLPCLPPGARTAEGPIMVLAGPLAVSLLLPSLTLLVSHLSSSQDVSSEPSSEQQLCALSKH PTVAFEDLQPWVSNFTYPGARDFSQLALDPSGNQLIVGARNYLFRLSLANVSLLQATE ASSEDTRRSCQSKGKTE EECQNYVRVLIVAGRKVFMCGTNAFSPMCTSRQVGNLSRTTEKINGVARCPYDPRH STAVISSQGELYAATVIDF SGRDPAIYRSLGSGPPLRTAQY SK LNEPNFVAAYDIGLFAYFFLRENAVEHDCGRTVYSRVARVCKNDVGGRFL LEDTWTTFMKARLNCSRPGEVPFYYNELQSAFHLPEQDLIYGVFTTNVNSIAASAVCAFNLSAISQAFNGPFRYQE NPRAAWLPIANPIPNFQCGTLPETGPNENLTERSLQDAQRLFLMSEAVQPVTPEPCVTQDSVRFSHLWDLVQAKD TLYHVLYIGTESGTILKALSTASRSLHGCYLEELHVLPPGRREPLRSLRILHSARALFVGLRDGVLRVPLERCAAY RSQGACLGARDPYCG DGKQQRCSTLEDSSNMSLWTQNITACPVRNVTRDGGFGP SPWQPCEHLDGDNSGSCLCR ARSCDSPRPRCGGLDCLGPAIHIA CSRNGAWTP SSWALCSTSCGIGFQVRQRSCSNPAPRHGGRICVGKSREER FCNENTPCPVPIF ASWGS S CSSNCGGGMQSRRRACENGNSCLGCGVEFKTCNPEGCPEVRRNTP TPWLPVNV TQGGARQEQRFRFTCRAPLADPHGLQFGRRRTETRTCPADGSGSCDTDALVEDLLRSGSTSPHTVSGGWAAWGPWS SCSRDCELGFRVRKRTCTNPEPRNGGLPCVGDAAEYQDCNPQACPVRGAWSCWTS SPCSASCGGGHYQRTRSCTS PAPSPGEDICLGLHTEEALCATQACPEGWSPWSEWSKCTDDGAQSRSRHCEELLPGSSACAGNSSQSRPCPYSEIP VILPASSMEEATGCAGFNLIHLVATGISCFLGSGLLTLAVYLSCQHCQRQSQESTLVHPATPNHLHYKGGGTPKNE KYTPMEFKTLMKNMLIPDDRAHFYPLQQTNVYTTTYYPSPLNKHSFRPEASPGQRCFPMS

The disclosed nucleic acid MOL4a sequence has 3226 of 3664 bases (88%) identical to a musculus semaphorin mRNA (GENBANK-ID: ACC: X97818).

The full amino acid sequence ofthe disclosed MOL4a polypeptide has 1021 of 1093 amino acid residues (93%) identical to, and 1053 of 1093 residues (96%) positive with, the 1093 amino acid residue semaphorin 5B precursor protein from Mus musculus (ptnr:SPTREMBL-ACC:O60519), and 971 of 973 amino acid residues (99%) identical to, and 972 of 973 residues (99%) positive with patp:AAY94990 Human secreted protein vb21_l, having 999 aa. The C-terminal 1202 amino acid residues of MOL4a are 100% identical to human IAA 1445 PROTEIN (TREMBLNEW-ACC:BAA95969).

MOL4a expression in different tissues was examined through TaqMan as described below in Example 1.

A SNP for MOL4a and the corresponding amino acid change it would cause is shown in Table 4C. The SNP was identified using the techniques disclosed in Example 3.

Table 4C: SNP for MOL4a

Consensus Base AA Residue Position Change Change Change Position

In a search of CuraGen's proprietary human expressed sequence assembly database, assemblies 11 1750277 (589 nucleotides) and 87739769 (896 nucleotides) were identified as having >95% homology to this predicted semaphorin sequence (Fig 3A2). This database is composed ofthe expressed sequences (as derived from isolated mRNA) from more than 96 different tissues. The mRNA is converted to cDNA and then sequenced. These expressed DNA sequences are then pooled in a database and those exhibiting a defined level of homology are combined into a single assembly with a common consensus sequence. The consensus sequence is representative of all member components. Since the nucleic acid ofthe described invention has >95% sequence identity with the CuraGen assembly, the nucleic acid ofthe invention likely represents an expressed semaphorin sequence.

The DNA assembly 111750277 has 3 components and was found by CuraGen to be expressed in the following tissues: Lymph node and Lung. The DNA assembly 87739769 has 7 components and was found by CuraGen to be expressed in the following tissues: Brain, Uterus, and Lung.

MOL4b

The disclosed novel semaphorin-like protein, MOL4b (also referred to herein as CG106951-02), is encoded by a nucleic acid, 4233 nucleotides long (SEQ ID NO:105). An open reading frame was identified beginning with an ATG initiation codon at nucleotides 2-4and ending with a TGA codon at nucleotides 3281-3283. Putative untranslated regions upstream from the initiation codon and downstream from the termination codon are underlined in Table 4D, and the start and stop codons are in bold letters.

Table 4D. MOL4b Nucleotide Sequence (SEQ ID NO:106).

CATGGTGCTTGCAGGCCCCCTGGCTGTCTCGCTGTTGCTGCCCAGCCTCACACTGCTGGTGTCCCACCTCT ;CAG CTCCCAGGATGTCTCCAGTGAGCCCAGCAGTGAGCAGCAGCTGTGCGCCCTTAGCAAGCACCCCACCGTG&3CTT TGAAGACCTGCAGCCGTGGGTCTCTAACTTCACCTACCCTGGAGCCCGGGATTTCTCCCAGCTGGCTTTGGACCC CTCCGGGAACCAGCTCATCGTGGGAGCCAGGAACTACCTCTTCAGACTCAGCCTTGCCAATGTCTCTCTTΓTTCA

GGCCACAGAGTGGGCCTCCAGTGAGGACACGCGCCGCTCCTGCCAAAGCAAAGGGAAGACTGAGGAGGAGT-^'ΪTCA

GAACTACGTGCGAGTCCTGATCGTCGCCGGCCGGAAGGTGTTCATGTGTGGAACCAATGCCTTTTCCCCCAΓGTG CACCAGCAGACAGGTGGGGAACCTCAGCCGGACTACTGAGAAGATCAATGGTGTGGCCCGCTGCCCCTATGACCC ACGCCACAACTCCACAGCTGTCATCTCCTCCCAGGGGGAGCTCTATGCAGCCACGGTCATCGACTTCTCAG;TCG GGACCCTGCCATCTACCGCAGCCTGGGCAGTGGGCCACCGCTTCGCACTGCCCAATATAACTCCAAGTGGCΓTAA TGAGCCAAACTTCGTGGCAGCCTATGATATTGGGCTGTTTGCATACTTCTTCCTGCGGGAGAACGCAGTGCAGCA CGACTGTGGACGCACCGTGTACTCTCGCGTGGCCCGCGTGTGCAAGAATGACGTGGGGGGCCGATTCCTGC GGA GGACACATGGACCACATTCATGAAGGCCCGGCTCAACTGCTCCCGCCCGGGCGAGGTCCCCTTCTACTATAACGA GCTGCAGAGTGCCTTCCACTTGCCAGAGCAGGACCTCATCTATGGAGTTTTCACAACCAACGTAAACAGCATCGC GGCTTCTGCTGTCTGCGCCTTCAACCTCAGTGCTATCTCCCAGGCTTTCAATGGCCCATTTCGCTACCAGGAGAA CCCCAGGGCTGCCTGGCTCCCCATAGCCAACCCCATCCCCAATTTCCAGTGTGGCACCCTGCCTGAGACCGGTCC CAACGAGAACCTGACGGAGCGCAGCCTGCAGGACGCGCAGCGCCTCTTCCTGATGAGCGAGGCCGTGCAGCCGGT GACACCCGAGCCCTGTGTCACCCAGGACAGCGTGCGCTTCTCACACCTCGTGGTGGACCTGGTGCAGGCTAAAGA CACGCTCTACCATGTACTCTACATTGGCACCGAGTCGGGCACCATCCTGAAGGCGCTGTCCACGGCGAGCCGCAG CCTCCACGGCTGCTACCTGGAGGAGCTGCACGTGCTGCCCCCCGGGCGCCGCGAGCCCCTGCGCAGCCTGCGCAT CCTGCACAGCGCCCGCGCGCTCTTCGTGGGGCTGAGAGACGGCGTCCTGCGGGTCCCACTGGAGAGGTGCGCCGC CTACCGCAGCCAGGGGGCATGCCTGGGGGCCCGGGACCCGTACTGTGGCTGGGACGGGAAGCAGCAACGTTGCAG CACACTCGAGGACAGCTCCAACATGAGCCTCTGGACCCAGAACATCACCGCCTGTCCTGTGCGGAATGTGACACG GGATGGGGGCTTCGGCCCATGGTCACCATGGCAACCATGTGAGCACTTGGATGGGGACAACTCAGGCTCTTGCCT GTGTCGAGCTCGATCCTGTGATTCCCCTCGACCCCGCTGTGGGGGCCTTGACTGCCTGGGGCCAGCCATCCACAT CGCCAACTGCTCCAGGAATGGGGCGTGGACCCCGTGGTCATCGTGGGCGCTGTGCAGCACGTCCTGTGGCATCGG CTTCCAGGTCCGCCAGCGAAGTTGCAGCAACCCTGCTCCCCGCCACGGGGGCCGCATCTGCGTGGGCAAGAGCCG GGAGGAACGGTTCTGTAATGAGAACACGCCTTGCCCGGTGCCCATCTTCTGGGCTTCCTGGGGCTCCTGGAGCAA GTGCAGCAGCAACTGTGGAGGGGGCATGCAGTCGCGGCGTCGGGCCTGCGAGAACGGCAACTCCTGCCTGGGCTG CGGCGTGGAGTTCAAGACGTGCAACCCCGAGGGCTGCCCCGAAGTGCGGCGCAACACCCCCTGGACGCCGTGGCT GCCCGTGAACGTGACGCAGGGCGGGGCACGGCAGGAGCAGCGGTTCCGCTTCACCTGCCGCGCGCCCCTTGCAGA CCCGCACGGCCTGCAGTTCGGCAGGAGAAGGACCGAGACGAGGACCTGTCCCGCGGACGGCTCCGGCTCCTGCGA CACCGACGCCCTGGTGGAGGACCTCCTGCGCAGCGGGAGCACCTCCCCGCACACGGTGAGCGGGGGCTGGGCCGC CTGGGGCCCGTGGTCGTCCTGCTCCCGGGACTGCGAGCTGGGCTTCCGCGTCCGCAAGAGAACGTGCACTAACCC GGAGCCCCGCAACGGGGGCCTGCCCTGCGTGGGCGATGCTGCCGAGTACCAGGACTGCAACCCCCAGGCTTGCCC AGTTCGGGGTGCTTGGTCCTGCTGGACCTCATGGTCTCCATGCTCAGCTTCCTGTGGTGGGGGTCACTATCAACG CACCCGTTCCTGCACCAGCCCCGCACCCTCCCCAGGTGAGGACATCTGTCTCGGGCTGCACACGGAGGAGGCACT ATGTGCCACACAGGCCTGCCCAGAAGGCTGGTCGCCCTGGTCTGAGTGGAGTAAGTGCACTGACGACGGAGCCCA GAGCCGAAGCCGGCACTGTGAGGAGCTCCTCCCAGGGTCCAGCGCCTGTGCTGGAAACAGCAGCCAGAGCCGCCC CTGCCCCTACAGCGAGATTCCCGTCATCCTGCCAGCCTCCAGCATGGAGGAGGCCACCGGCTGTGCAGGGTTCAA TCTCATCCACTTGGTGGCCACGGGCATCTCCTGCTTCTTGGGCTCTGGGCTCCTGACCCTAGCAGTGTACCTGTC TTGCCAGCACTGCCAGCGTCAGTCCCAGGAGTCCACACTGGTCCATCCTGCCACCCCCAACCATTTGCACTACAA GGGCGGAGGCACCCCGAAGAATGAAAAGTACACACCCATGGAATTCAAGACCCTGAACAAGAATAACTTGATCCC TGATGACAGAGCCAACTTCTACCCATTGCAGCAGACCAATGTGTACACGACTACTTACTACCCAAGCCCCCTGAA CAAACACAGCTTCCGGCCCGAGGCCTCACCTGGACAACGGTGCTTCCCCAACAGCTGATACCGCCGTCCTGGGGA CTTGGGCTTCTTGCCTTCATAAGGCACAGAGCAGATGGAGATGGGACAGTGGAGCCAGTTTGGTTTTCTCCCTCT GCACTAGGCCAAGAACTTGCTGCCTTGCCTGTGGGGGGTCCCATCCGGCTTCAGAGAGCTCTGGCTGGCATTGAC CATGGGGGAAAGGGCTGGTTTCAGGCTGACATATGGCCGCAGGTCCAGTTCAGCCCAGGTCTCTCATGGTTATCT TCCAACCCACTGTCACGCTGACACTATGCTGCCATGCCTGGGCTGTGGACCTACTGGGCATTTGAGGAACTGGAG AATGGAGATGGCAAGAGGGCAGGCTTTTAAGTTTGGGTTGGAGACAACTTCCTGTGGCCCCCACAAGCTGAGTCT GGCCTTCTCCAGCTGGCCCCAAAAAAGGCCTTTGCTACATCCTGATTATCTCTGAAAGTAATCAATCAAGTGGCT CCAGTAGCTCTGGATTTTCTGCCAGGGCTGGGCCATTGTGGTGCTGCCCCAGTATGACATGGGACCAAGGCCAGC GCAGGTTATCCACCTCTGCCTGGAAGTCTATACTCTACCCAGGGCATCCCTCTGGTCAGAGGCAGTGAGTACTGG GAACTGGAGGCTGACCTGTGCTTAGAAGTCCTTTAATCTGGGCTGGTACAGGCCTCAGCCTTGCCCTCAATGCAC GAAAGGTGGCCCAGGAGAGAGGATCAATGCCACAGGAGGCAGAAGTCTGGCCTCTGTGCCTCTATGGAGACTATC TTCCAGTTGCTGCTCAACAGAGTTGTTGGCTGAGACCTGCTTGGGAGTCTCTGCTGGCCCTTCATCTGTTCAGGA ACACACACACACACACACTCACACACGCACACACAATCACAATTTGCTACAGCAACAAAAAAGACATTGGGCTGT GGCATTATTAATTAAAGATGATATCCAGTCTCC

The 1093 amino acid MOL4b polypeptide (SEQ ID NO: 106) encoded by SEQ ID NO: 105 is presented using the one-letter amino acid code in Table 4E. The Psort profile for MOL4b predicts that this sequence has no signal peptide and is likely to be a Type II (Ncyt Cexo) membrane protein with a certainty of0.7900.

Table 4E. MOL4b protein sequence (SEQ ID NO.106)

MVLAGPLAVSLLLPSLTLLVSHLSSSQDVSSEPSSEQQLCALSKHPTVAFEDLQPWVSNFTYPGARDFSQLALDPS GNQLIVGARNYLFRLSLA VSLLQATE ASSEDTRRSCQSKGKTEEECQNYVRVLIVAGRKVFMCGTNAFSPMCTS RQVGNLSRTTEKINGVARCPYDPRHNSTAVISSQGELYAATVIDFSGRDPAIYRSLGSGPPLRTAQYNSKWLNEPN FVAAYDIGLFAYFFLRENAVEHDCGRTVYSRVARVCK DVGGRFLLEDT TTFMKARLNCSRPGEVPFYYNELQSA FHLPEQDLIYGVFTTNVNSIAASAVCAFNLSAISQAFNGPFRYQENPRAAWLPIANPIPNFQCGTLPETGPNENLT ERSLQDAQRLFLMSEAVQPVTPEPCVTQDSVRFSHLWDLVQAKDTLYHVLYIGTESGTILKALSTASRSLHGCYL EELHVLPPGRREPLRSLRILHSARALFVGLRDGVLRVPLERCAAYRSQGACLGARDPYCGWDG QQRCSTLEDSSN MSLWTQMITACPVRVTRDGGFGPWSPWQPCEHLDGDNSGSCLCRARSCDSPRPRCGGLDCLGPAIHIANCSRNGA WTPWSSWALCSTSCGIGFQVRQRSCSNPAPRHGGRICVGKSREERFCNENTPCPVPIFWASWGSWSKCSSNCGGGM QSRRRACENGNSCLGCGVEFKTCNPEGCPEVRRNTPWTP LPVNVTQGGARQEQRFRFTCRAPLADPHGLQFGRRR TETRTCPADGSGSCDTDALVEDLLRSGSTSPHTVSGGWAA GP SSCSRDCELGFRVRKRTCTNPEPRNGGLPCVG DAAEYQDCNPQACPVRGA SC TS SPCSASCGGGHYQRTRSCTSPAPSPGEDICLGLHTEEALCATQACPEG SP WSEWSKCTDDGAQSRSRHCEELLPGSSACAGNSSQSRPCPYSEIPVILPASSMEEATGCAGFLIHLVATGISCFL GSGLLTLAVYLSCQHCQRQSQESTLVHPATPNHLHYKGGGTPKNEKYTPMEFKTLNKNNLIPDDRANFYPLQQTNV YTTTYYPSPLNKHSFRPEASPGQRCFPNS

The disclosed nucleic acid MOL4b sequence has 3864 of 3873 (99%) identical to an alpha gene treating neurodegenerative disorders, autoimmune diseases and cancer (WO200011015-Al). The disclosed MOOL4b nucleic acid is also 100% identical to Kiaa 1445.

The full amino acid sequence ofthe disclosed MOL4b polypeptide has 972 of 973 amino acid residues (99%) identical to the alpha gene treating neurodegenerative disorders, autoimmune diseases and cancer (WO20001 1015-Al). The disclosed MOL4b polypeptide is also 100% identical to Kiaa 1445. The disclosed MOL4b polypeptide is also 93% identical to mouse semaphorin.

Analysis ofthe MOL4b sequence against the Pfam database showed that the sequence contains a Sema domain, a Thrombospondin type 1 domain, and a Plexin repeat

MOL4c

The disclosed novel semaphorin-like protein, MOL4c (also referred to herein as CG106951-04), is encoded by a nucleic acid, 3631 nucleotides long (SEQ ID NO:107). An open reading frame was identified beginning with an ATG initiation codon at nucleotides 154-156 and ending with a TGA codon at nucleotides 3544-3546. Putative untranslated regions upstream from the initiation codon and downstream from the termination codon are underlined in Table 4F, and the start and stop codons are in bold letters.

Table 4F. MOL4c Nucleotide Sequence (SEQ ED NO: 107).

GCGGCCGCCCCATTCCCAGACCGGCCGCCAGCCCATCTGGTTAGCTCCCGCCGCTCCGCGCCGCCCGGGAGTCGG GAGCCGCGGGGAACCGGGCACCTGCACCCGCCTCTGGGAGTGAGTGGTTCCAGCTGGTGCCTGGCCTGTGTCTCT TGGATGCCCTGTGGCTTCAGTCCGTCTCCTGTTGCCCACCACCTCGTCCCTGGGCCGCCTGATACCCCAGCCCAA CAGCTAAGGTGTGGATGGACAGTAGGGGGCTGGCTTCTCTCACTGGTCAGGGGTCTTCTCCCCTGTCTGCCTCCC GGAGCTAGGACTGCAGAGGGGCCTATCATGGTGCTTGCAGGCCCCCTGGCTGTCTCGCTGTTGCTGCCCAGCCTC ACACTGCTGGTGTCCCACCTCTCCAGCTCCCAGGATGTCTCCAGTGAGCCCAGCAGTGAGCAGCAGCTGTGCGCC CTTAGCAAGCACCCCACCGTGGCCTTTGAAGACCTGCAGCCGTGGGTCTCTAACTTCACCTACCCTGGAGCCCGG GATTTCTCCCAGCTGGCTTTGGACCCCTCCGGGAACCAGCTCATCGTGGGAGCCAGGAACTACCTCTTCAGACTC AGCCTTGCCAATGTCTCTCTTCTTCAGGCCACAGAGTGGGCCTCCAGTGAGGACACGCGCCGCTCCTGCCAAAGC AAAGGGAAGACTGAGGAGGAGTGTCAGAACTACGTGCGAGTCCTGATCGTCGCCGGCCGGAAGGTGTTCATGTGT GGAACCAATGCCTTTTCCCCCATGTGCACCAGCAGACAGGTGGGGAACCTCAGCCGGACTACTGAGAAGATCAAT GGTGTGGCCCGCTGCCCCTATGACCCACGCCACAACTCCACAGCTGTCATCTCCTCCCAGGGGGAGCTCTATGCA GCCACGGTCATCGACTTCTCAGGTCGGGACCCTGCCATCTACCGCAGCCTGGGCAGTGGGCCACCGCTTCGCACT GCCCAATATAACTCCAAGTGGCTTAATGAGCCAAACTTCGTGGCAGCCTATGATATTGGGCTGTTTGCATACTTC TTCCTGCGGGAGAACGCAGTGGAGCACGACTGTGGACGCACCGTGTACTCTCGCGTGGCCCGCGTGTGCAAGAAT GACGTGGGGGGCCGATTCCTGCTGGAGGACACATGGACCACATTCATGAAGGCCCGGCTCAACTGCTCCCGCCCG GGCGAGGTCCCCTTCTACTATAACGAGCTGCAGAGTGCCTTCCACTTGCCAGAGCAGGACCTCATCTATGGAGTT TTCACAACCAACGTAAACAGCATCGCGGCTTCTGCTGTCTGCGCCTTCAACCTCAGTGCTATCTCCCAGGCTTTC AATGGCCCATTTCGCTACCAGGAGAACCCCAGGGCTGCCTGGCTCCCCATAGCCAACCCCATCCCCAATTTCCAG TGTGGCACCCTGCCTGAGACCGGTCCCAACGAGAACCTGACGGAGCGCAGCCTGCAGGACGCGCAGCGCCTCTTC CTGATGAGCGAGGCCGTGCAGCCGGTGACACCCGAGCCCTGTGTCACCCAGGACAGCGTGCGCTTCTCACACCTC GTGGTGGACCTGGTGCAGGCTAAAGACACGCTCTACCATGTACTCTACATTGGCACCGAGTCGGGCACCATCCTG AAGGCGCTGTCCACGGCGAGCCGCAGCCTCCACGGCTGCTACCTGGAGGAGCTGCACGTGCTGCCCCCCGGGCGC CGCGAGCCCCTGCGCAGCCTGCGCATCCTGCACAGCGCCCGCGCGCTCTTCGTGGGGCTGAGAGACGGCGTCCTG CGGGTCCCACTGGAGAGGTGCGCCGCCTACCGCAGCCAGGGGGCATGCCTGGGGGCCCGGGACCCGTACTGTGGC TGGGACGGGAAGCAGCAACGTTGCAGCACACTCGAGGACAGCTCCAACATGAGCCTCTGGACCCAGAACATCACC GCCTGTCCTGTGCGGAATGTGACACGGGATGGGGGCTTCGGCCCATGGTCACCATGGCAACCATGTGAGCACTTG GATGGGGACAACTCAGGCTCTTGCCTGTGTCGAGCTCGATCCTGTGATTCCCCTCGACCCCGCTGTGGGGGCCTT GACTGCCTGGGGCCAGCCATCCACATCGCCAACTGCTCCAGGAATGGGGCGTGGACCCCGTGGTCATCGTGGGCG CTGTGCAGCACGTCCTGTGGCATCGGCTTCCAGGTCCGCCAGCGAAGTTGCAGCAACCCTGCTCCCCGCCACGGG GGCCGCATCTGCGTGGGCAAGAGCCGGGAGGAACGGTTCTGTAATGAGAACACGCCTTGCCCGGTGCCCATCTTC TGGGCTTCCTGGGGCTCCTGGAGCAAGTGCAGCAGCAACTGTGGAGGGGGCATGCAGTCGCGGCGTCGGGCCTGC GAGAACGGCAACTCCTGCCTGGGCTGCGGCGTGGAGTTCAAGACGTGCAACCCCGAGGGCTGCCCCGAAGTGCGG CGCAACACCCCCTGGACGCCGTGGCTGCCCGTGAACGTGACGCAGGGCGGGGCACGGCAGGAGCAGCGGTTCCGC TTCACCTGCCGCGCGCCCCTTGCAGACCCGCACGGCCTGCAGTTCGGCAGGAGAAGGACCGAGACGAGGACCTGT CCCGCGGACGGCTCCGGCTCCTGCGACACCGACGCCCTGGTGGAGGACCTCCTGCGCAGCGGGAGCACCTCCCCG CACACGGTGAGCGGGGGCTGGGCCGCCTGGGGCCCGTGGTCGTCCTGCTCCCGGGACTGCGAGCTGGGCTTCCGC GTCCGCAAGAGAACGTGCACTAACCCGGAGCCCCGCAACGGGGGCCTGCCCTGCGTGGGCGATGCTGCCGAGTAC CAGGACTGCAACCCCCAGGCTTGCCCAGTTCGGGGTGCTTGGTCCTGCTGGACCTCATGGTCTCCATGCTCAGCT TCCTGTGGTGGGGGTCACTATCAACGCACCCGTTCCTGCACCAGCCCCGCACCCTCCCCAGAAGGCTGGTCGCCC TGGTCTGAGTGGAGTAAGTGCACTGACGACGGAGCCCAGAGCCGAAGCCGGCACTGTGAGGAGCTCCTCCCAGGG TCCAGCGCCTGTGCTGGAAACAGCAGCCAGAGCCGCCCCTGCCCCTACAGCGAGATTCCCGTCATCCTGCCAGCC TCCAGCATGGAGGAGGCCACCGGCTGTGCAGGGTTCAATCTCATCCACTTGGTGGCCACGGGCATCTCCTGCTTC TTGGGCTCTGGGCTCCTGACCCTAGCAGTGTACCTGTCTTGCCAGCACTGCCAGCGTCAGTCCCAGGAGTCCACA CTGGTCCATCCTGCCACCCCCAACCATTTGCACTACAAGGGCGGAGGCACCCCGAAGAATGAAAAGTACACACCC ATGGAATTCAAGACCCTGAACAAGAATAACTTGATCCCTGATGACAGAGCCAACTTCTACCCATTGCAGCAGACC AATGTGTACACGACTACTTACTACCCAAGCCCCCTGAACAAACACAGCTTCCGGCCCGAGGCCTCACCTGGACAA CGGTGCTTCCCCAACAGCTGATACCGCCGTCCTGGGGACTTGGGCTTCTTGCCTTCATAAGGCACAGAGCAGATG GAGATGGGACAGTGGAGCCAGTTTGGTTTCT

The nucleic acid MOL4c ofthe invention , localized to human chromosome 3, was found, using a BLASTN search to have 31 17 of 3221 (99%) nucleotides identical to the 4559 nucleotide mRNA for KIAA 1445 protein from Homo sapiens (GENBANK- ID:AB040878|acc:AB040878) (E = 0.0). It also has 678 of 678 (100%) nucleotides identical to the 819 nucleotide sequence for NT2RM2 Homo sapiens cDNA clone NT2RM2001930 5', mRNA sequence (GENBANK-ID:AU 124266|acc:AU 124266.1 AU124266) (E = 5.2e^"147).

The 1 130 amino acid MOL4c polypeptide (SEQ ID NO: 108) encoded by SEQ ID NO: 107 is presented using the one-letter amino acid code in Table 4G. The Psort profile for MOL4c predicts that this sequence has a signal peptide between amino acids 42 and 43 (VRG-LL). It is also likely to be localized to the plasma membrane with a certainty of 0.7900. In other embodiments, MOL4c could also be localized to the microbody (peroxisome) with a certainty of 0.3000, to the Golgi body with a certainty of 0.3000,or to the endoplasmic reticulum (membrane) with a certainty of 0.2000. Table 4G. MOL4c protein sequence (SEQ ID NO:108)

MPCGFSPSPVAHHLVPGPPDTPAQQLRCGWTVGGWLLSLVRGLLPCLPPGARTAEGPIMVLAGPLAVSLLLPSLTL LVSHLSSSQDVSSEPSSEQQLCALSKHPTVAFEDLQP VSNFTYPGARDFSQLALDPSGNQLIVGAR YLFRLSLA NVSLLQATEWASSEDTRRSCQSKGKTEEECQNYVRVLIVAGRKVFMCGTNAFSPMCTSRQVGNLSRTTEKINGVAR CPYDPRHNSTAVISSQGELYAATVIDFSGRDPAIYRSLGSGPPLRTAQYNSKWLNEPNFVAAYDIGLFAYFFLREN AVEHDCGRTVYSRVARVC NDVGGRFLLEDTWTTFMKARLNCSRPGEVPFYYNELQSAFHLPEQDLIYGVFTTNVN SIAASAVCAFNLSAISQAFNGPFRYQENPRAAWLPIANPIPNFQCGTLPETGPNENLTERSLQDAQRLFLMSEAVQ PVTPEPCVTQDSVRFSHLWDLVQAKDTLYHVLYIGTESGTILKALSTASRSLHGCYLEELHVLPPGRREPLRSLR ILHSARALFVGLRDGVLRVPLERCAAYRSQGACLGARDPYCGWDGKQQRCSTLEDSSNMSLWTQNITACPVRNVTR DGGFGP SP QPCEHLDGDNSGSCLCRARSCDSPRPRCGGLDCLGPAIHIANCSRNGA TPWSSWALCSTSCGIGF QVRQRSCSNPAPRHGGRICVGKSREERFCNENTPCPVPIFWASWGSWSKCSSNCGGGMQSRRRACENGNSCLGCGV EFKTCNPEGCPEVRRNTPWTP LPVNVTQGGARQEQRFRFTCRAPLADPHGLQFGRRRTETRTCPADGSGSCDTDA LVEDLLRSGSTSPHTVSGGWAAWGPWSSCSRDCELGFRVRKRTCTNPEPRNGGLPCVGDAAEYQDCNPQACPVRGA WSC TS SPCSASCGGGHYQRTRSCTSPAPSPEG SP SE SKCTDDGAQSRSRHCEELLPGSSACAGNSSQSRPC PYSEIPVILPASSMEEATGCAGFNLIHLVATGISCFLGSGLLTLAVYLSCQHCQRQSQESTLVHPATPNHLHYKGG GTPKNEKYTPMEF TLNKWNLIPDDRANFYPLQQTNVYTTTYYPSPLNKHSFRPEASPGQRCFPNS

The disclosed amino acid MOL4c sequence has 964 of 1010 amino acids (95%) identical to and 971 of 1010 amino acids (96%) positive with the 1202 namino acid sequence for KIAA1445 Protein from Homo sapiens (Human) (SPTREMBL- ACC:Q9P283) (E = 0.0).

MOL4c is expressed in at least NT2 teratocarcinoma cell line. Expression information was derived from the tissue sources ofthe sequences that were included in the derivation ofthe sequence of MOL4c.

The presence of identifiable domains in the protein disclosed herein was determined by searches versus domain databases such as Pfam, PROSITE, ProDom,

Blocks or Prints and then identified by the Interpro domain accession number. Significant domains are summarized in Table 4H.

Table 4H Domain Searh for MOL4c

Scores for sequence family classification (score includes all domains) : Model Description Score E- value N

Sema (InterPro) Sema domain 682.4 2.3e- 201 1 tsp 1 (InterPro) Thrombospondin type 1 domain 119.4 6.5e-

32 6

Plexin repeat (InterPro) Plexin repeat 61.0 2.5e-

14 1

Note: Please compare the score with TC (trusted cutoff) and NC (noise cutoff) scores in each model to evaluate its significance. More on Pfam Scores

Parsed for domains :

Model Domain seq-f seq-t hmm- -f hmm-t score E- -value

Sema 1/1 126 537 . 1 490 [] 682.4 2.; 3e-201

Plexin repeat 1/1 555 602 . 1 67 [] 61 .0 2 .5e-14 tsp 1 1/6 613 661 . 1 54 π -3 .9 1.9 tsp_l 2/6 668 719 . 1 54 [] 55. .3 1 .4e-12 tsp_l 3 / 6 726 770 . . 1 54 [ ] 33 . 4 5 . 1e- 06 tsp_l 4 / 6 857 907 . . 1 54 [] 48 . 7 1 . 3e- 10 tsp_l 5 / 6 914 946 . . 1 54 [ ] 2 . 6 0 . 35 tsp_l 6/ 6 948 988 . . 1 54 [ ] 20 . 9 0 . 0027

The Sema domain occurs in semaphorins, which are a large family of secreted and transmembrane proteins, some of which function as repellent signals during axon guidance. Sema domains also occur in a hepatocyte growth factor receptor, in SEX protein and in viral proteins. Plexin repeats have been found in plexins, semaphorins and integrins. Plexin is involved in the development of neural and epithelial tissues; semaphorins induce the collapse and paralysis of neuronal growth cones; and integrins may mediate adhesive or migratory functions of epithelial cells.

Thrombospondin type 1 domain repeat was first found in the thrombospondin protein where it is repeated 3 times. Now a number of proteins involved in the complement pathway (properdin, C6, C7, C8A, C8B, C9) as well as extracellular matrix protein like mindin, F-spondin, SCO-spondin and even the circumsporozoite surface protein 2 and TRAP proteins of Plasmodium contain one or more instance of this repeat. It has been involved in cell-cell interraction, inhibition of angiogenesis, apoptosis. MOL4d

The disclosed novel semaphorin-like protein, MOL4d (also referred to herein as 209829549), is encoded by a nucleic acid, 1203 nucleotides long (SEQ ID NO: 109). An open reading frame was identified beginning with an GGA initiation codon at nucleotides 1-3 and ending after a GAC codon at nucleotides 1201-1203. In Table 41, the start codon is in bold letters. Because the start and stop codons are not traditional initiation and termination codons, MOL4d could be a partial reading frame that extends further in the 5' and/or 3' directions.

Table 41. MOL4d Nucleotide Sequence (SEQ ID NO: 109).

GGATCCGGCCCATGGTCACCATGGCAACCATGTGAGCACTTGGATGGGGACAACTCAGGCTCTTGCCTGTGTCGA GCTCGATCCTGTGATTCCCCTCGACCCCGCTGTGGGGGCCTTGACTGCCTGGGGCCAGCCATCCACATCGCCAAC TGCTCCAGGAATGGGGCGTGGACCCCGTGGTCATCGTGGGCGCTGTGCAGCACGTCCTGTGGCATCGGCTTCCAG GTCCGCCAGCGAAGTTGCAGCAACCCTGCTCCCCGCCACGGGGGCCGCATCTGCGTGGGCAAGAGCCGGGAGGAA CGGTTCTGTAATGAGAACACGCCTTGCCCGGTGCCCATCTTCTGGGCTTCCTGGGGCTCCTGGAGCAAGTGCAGC AGCAACTGTGGAGGGGGCATGCGGTCGCGGCGTCGGGCCTGCGAGAACGGCAACTCCTGCCTGGGCTGCGGCGTG GAGTTCAAGACGTGCAACCCCGAGGGCTGCCCCGAAGTGCGGCGCAACACCCCCTGGACGCCGTGGCTGCCCGTG AACGTGACGCAGGGCGGGGCACGGCAGGAGCAGCGGTTCCGCTTCACCTGCCGCGCGCCCCTTGCAGACCCGCAC GGCCTGCAGTTCGGCAGGAGAAGGACCGAGACGAGGACCTGTCCCGCGGACGGCTCCGGCTCCTGCGACACCGAC GCCCTGGTGGAGGACCTCCTGCGCAGCGGGAGCACCTCCCCGCACACGGTGAGCGGGGGCTGGGCCGCCTGGGGC CCGTGGTCGTCCTGCTCCCGGGACTGCGAGCTGGGCTTCCGCGTCCGCAAGAGAACGTGCACTAACCCGGAGCCC CGCAACGGGGGCCTGCCCTGCGTGGGCGATGCTGCCGAGTACCAGGACTGCAACCCCCAGGCTTGCCCAGTTCGG GGTGCTTGGTCCTGCTGGACCTCATGGTCTCCATGCTCAGCTTCCTGTGGTGGGGGTCACTATCAACGCACCCGT TCCTGCACCAGCCCCGCACCCTCCCCAGGTGAGGACATCTGTCTCGGGCTGCACACGGAGGAGGCACTATGTGCC ACACAGGCCTGCCCAGAAGGCTGGTCGCCCTGGTCTGAGTGGAGTAAGTGCACTGACGACGGAGCCCAGAGCCGA AGCCGGCACTGTGAGGAGCTCCTCCCAGGGTCCAGCGCCTGTGCTGGAAACAGCAGCCAGAGCCGCCCCTGCGTC GAC

The reverse complement for MOL4d is shown in Table 4J.

Table 4J. MOL4d Nucleotide Sequence reverse complement (SEQ ID NO:110).

GTCGACGCAGGGGCGGCTCTGGCTGCTGTTTCCAGCACAGGCGCTGGACCCTGGGAGGAGCTCCTCACAGTGCCG GCTTCGGCTCTGGGCTCCGTCGTCAGTGCACTTACTCCACTCAGACCAGGGCGACCAGCCTTCTGGGCAGGCCTG TGTGGCACATAGTGCCTCCTCCGTGTGCAGCCCGAGACAGATGTCCTCACCTGGGGAGGGTGCGGGGCTGGTGCA GGAACGGGTGCGTTGATAGTGACCCCCACCACAGGAAGCTGAGCATGGAGACCATGAGGTCCAGCAGGACCAAGC ACCCCGAACTGGGCAAGCCTGGGGGTTGCAGTCCTGGTACTCGGCAGCATCGCCCACGCAGGGCAGGCCCCCGTT GCGGGGCTCCGGGTTAGTGCACGTTCTCTTGCGGACGCGGAAGCCCAGCTCGCAGTCCCGGGAGCAGGACGACCA CGGGCCCCAGGCGGCCCAGCCCCCGCTCACCGTGTGCGGGGAGGTGCTCCCGCTGCGCAGGAGGTCCTCCACCAG GGCGTCGGTGTCGCAGGAGCCGGAGCCGTCCGCGGGACAGGTCCTCGTCTCGGTCCTTCTCCTGCCGAACTGCAG GCCGTGCGGGTCTGCAAGGGGCGCGCGGCAGGTGAAGCGGAACCGCTGCTCCTGCCGTGCCCCGCCCTGCGTCAC GTTCACGGGCAGCCACGGCGTCCAGGGGGTGTTGCGCCGCACTTCGGGGCAGCCCTCGGGGTTGCACGTCTTGAA CTCCACGCCGCAGCCCAGGCAGGAGTTGCCGTTCTCGCAGGCCCGACGCCGCGACCGCATGCCCCCTCCACAGTT GCTGCTGCACTTGCTCCAGGAGCCCCAGGAAGCCCAGAAGATGGGCACCGGGCAAGGCGTGTTCTCATTACAGAA CCGTTCCTCCCGGCTCTTGCCCACGCAGATGCGGCCCCCGTGGCGGGGAGCAGGGTTGCTGCAACTTCGCTGGCG GACCTGGAAGCCGATGCCACAGGACGTGCTGCACAGCGCCCACGATGACCACGGGGTCCACGCCCCATTCCTGGA GCAGTTGGCGATGTGGATGGCTGGCCCCAGGCAGTCAAGGCCCCCACAGCGGGGTCGAGGGGAATCACAGGATCG AGCTCGACACAGGCAAGAGCCTGAGTTGTCCCCATCCAAGTGCTCACATGGTTGCCATGGTGACCATGGGCCGGA TCC

The 401 amino acid MOL4d polypeptide (SEQ ID NO:l l 1) encoded by SEQ ID NO: 109 is presented using the one-letter amino acid code in Table 4K.

Table 4K. MOL4d protein sequence (SEQ ID NO:lll)

GSGP SP QPCEHLDGDNSGSCLCRARSCDSPRPRCGGLDCLGPAIHIANCSRNGAWTPWSS ALCSTSCGIGFQV RQRSCSNPAPRHGGRICVGKSREERFCNENTPCPVPIFWASWGSWSKCSSNCGGGMRSRRRACENGNSCLGCGVEF KTCNPEGCPEVRRNTPWTP LPVNVTQGGARQEQRFRFTCRAPLADPHGLQFGRRRTETRTCPADGSGSCDTDALV EDLLRSGSTSPHTVSGG AA GP SSCSRDCELGFRVRKRTCTNPEPRNGGLPCVGDAAEYQDCNPQACPVRGA S C TS SPCSASCGGGHYQRTRSCTSPAPSPGEDICLGLHTEEALCATQACPEGWSP SEWSKCTDDGAQSRSRHCE ELLPGSSACAGNSSQSRPCVD

MOL4e

The disclosed novel semaphorin-like protein, MOL4e (also referred to herein as 209829553), is encoded by a nucleic acid, 1203 nucleotides long (SEQ ID NO:l 12). An open reading frame was identified beginning with an GGA initiation codon at nucleotides 1-3 and ending after a GAC codon at nucleotides 1201-1203. In Table 4L, the start codon is in bold letters. Because the start and stop codons are not traditional initiation and termination codons, MOL4e could be a partial reading frame that extends further in the 5' and/or 3' directions. Table 4L. MOL4e Nucleotide Sequence (SEQ ID NO: 112).

GGATCCGGCCCATGGTCACCATGGCAACCATGTGAGCACTTGGATGGGGACAACTCAGGCTCTTGCCTGTGTCGA GCTCGATCCTGTGATTCCCCTCGACCCCGCTGTGGGGGCCTTGACTGCCTGGGGCCAGCCATCCACATCGCCAAC TGCTCCAGGAATGGGGCGTGGACCCCGTGGTCATCGTGGGCGCTGTGCAGCACGTCCTGTGGCATCGGCTTCCAG GTCCGCCAGCGAAGTTGCAGCAACCCTGCTCCCCGCCACGGGGGCCGCATCTGCGTGGGCAAGAGCCGGGAGGAA CGGTTCTGTAATGAGAACACGCCTTGCCCGGTGCCCATCTTCTGGGCTTCCTGGGGCTCCTGGAGCAAGTGCAGC AGCAACTGTGGAGGGGGCATGCAGTCGCGGCGTCGGGCCTGCGAGAACGGCAACTCCTGCCTGGGCTGCGGCGTG GAGTTCAAGACGTGCAACCCCGAGGGCTGCCCCGAAGTGCGGCGCAACACCCCCTGGACGCCGTGGCTGCCCGTG AACGTGACGCAGGGCGGGGCACGGCAGGAGCAGCGGTTCCGCTTCACCTGCCGCGCGCCCCTTGCAGACCCGCAC GGCCTGCAGTTCGGCAGGAGAAGGACCGAGACGAGGACCTGTCCCGCGGACGGCTCCGGCTCCTGCGACACCGAC GCCCTGGTGGAGGACCTCCTGCGCAGCGGGAGCACCTCCCCGCACACGGTGAGCGGGGGCTGGGCCGCCTGGGGC CCGTGGTCGTCCTGCTCCCGGGACTGCGAGCTGGGCTTCCGCGTCCGCAAGAGAACGTGCACTAACCCGGAGTCC CGCAACGGGGGCCTGCCCTGCGTGGGCGATGCTGCCGAGTACCAGGACTGCAACCCCCAGGCTTGCCCAGTTCGG GGTGCTTGGTCCTGCTGGACCTCATGGTCTCCATGCTCAGCTTCCTGTGGTGGGGGTCACTATCAACGCACCCGT TCCTGCACCAGCCCCGCACCCTCCCCAGGTGAGGACATCTGTCTCGGGCTGCACACGGAGGAGGCACTATGTGCC ACACAGGCCTGCCCAGAAGGCTGGTCGCCCTGGTCTGAGTGGAGTAAGTGCACTGACGACGGAGCCCAGAGCCGA AGCCGGCACTGTGAGGAGCTCCTCCCAGGGTCCAGCGCCTGTGCTGGAAACAGCAGCCAGAGCCGCCCCTGCGTC GAC

The reverse complement for MOL4e is shown in Table 4M.

Table 4M. MOL4e Nucleotide Sequence reverse complement (SEQ ID

NO:113).

GTCGACGCAGGGGCGGCTCTGGCTGCTGTTTCCAGCACAGGCGCTGGACCCTGGGAGGAGCTCCTCACAGTGCCG GCTTCGGCTCTGGGCTCCGTCGTCAGTGCACTTACTCCACTCAGACCAGGGCGACCAGCCTTCTGGGCAGGCCTG TGTGGCACATAGTGCCTCCTCCGTGTGCAGCCCGAGACAGATGTCCTCACCTGGGGAGGGTGCGGGGCTGGTGCA GGAACGGGTGCGTTGATAGTGACCCCCACCACAGGAAGCTGAGCATGGAGACCATGAGGTCCAGCAGGACCAAGC ACCCCGAACTGGGCAAGCCTGGGGGTTGCAGTCCTGGTACTCGGCAGCATCGCCCACGCAGGGCAGGCCCCCGTT GCGGGACTCCGGGTTAGTGCACGTTCTCTTGCGGACGCGGAAGCCCAGCTCGCAGTCCCGGGAGCAGGACGACCA CGGGCCCCAGGCGGCCCAGCCCCCGCTCACCGTGTGCGGGGAGGTGCTCCCGCTGCGCAGGAGGTCCTCCACCAG GGCGTCGGTGTCGCAGGAGCCGGAGCCGTCCGCGGGACAGGTCCTCGTCTCGGTCCTTCTCCTGCCGAACTGCAG GCCGTGCGGGTCTGCAAGGGGCGCGCGGCAGGTGAAGCGGAACCGCTGCTCCTGCCGTGCCCCGCCCTGCGTCAC GTTCACGGGCAGCCACGGCGTCCAGGGGGTGTTGCGCCGCACTTCGGGGCAGCCCTCGGGGTTGCACGTCTTGAA CTCCACGCCGCAGCCCAGGCAGGAGTTGCCGTTCTCGCAGGCCCGACGCCGCGACTGCATGCCCCCTCCACAGTT GCTGCTGCACTTGCTCCAGGAGCCCCAGGAAGCCCAGAAGATGGGCACCGGGCAAGGCGTGTTCTCATTACAGAA CCGTTCCTCCCGGCTCTTGCCCACGCAGATGCGGCCCCCGTGGCGGGGAGCAGGGTTGCTGCAACTTCGCTGGCG GACCTGGAAGCCGATGCCACAGGACGTGCTGCACAGCGCCCACGATGACCACGGGGTCCACGCCCCATTCCTGGA GCAGTTGGCGATGTGGATGGCTGGCCCCAGGCAGTCAAGGCCCCCACAGCGGGGTCGAGGGGAATCACAGGATCG AGCTCGACACAGGCAAGAGCCTGAGTTGTCCCCATCCAAGTGCTCACATGGTTGCCATGGTGACCATGGGCCGGA TCC

The 401 amino acid MOL4e polypeptide (SEQ ID NO: 114) encoded by SEQ ID 12 is presented using the one-letter amino acid code in Table 4N.

Table 4N. MOL4e protein sequence (SEQ ID NO: 114)

GSGP SP QPCEHLDGDNSGSCLCRARSCDSPRPRCGGLDCLGPAIHIANCSRNGA TPWΞS ALCSTSCGIGFQV RQRSCSNPAPRHGGRICVGKSREERFCNENTPCPVPIFWASWGSWSKCSSNCGGGMQSRRRACENGNSCLGCGVEF KTCNPEGCPEVRRNTPWTPWLPV VTQGGARQEQRFRFTCRAPLADPHGLQFGRRRTETRTCPADGSGSCDTDALV EDLLRSGSTSPHTVSGGWAAWGPWSSCSRDCELGFRVRKRTCTNPESRNGGLPCVGDAAEYQDCNPQACPVRGAWS C TS SPCSASCGGGHYQRTRSCTSPAPSPGEDICLGLHTEEALCATQACPEG SPWSEWSKCTDDGAQSRSRHCE ELLPGSSACAGNSSQSRPCVD

MOL4f

The disclosed novel semaphorin-like protein, MOL4f (also referred to herein as 9642), is encoded by a nucleic acid, 1203 nucleotides long (SEQ ID NO:l 15). An open reading frame was identified beginning with an GGA initiation codon at nucleotides 1-3 and ending after a GAC codon at nucleotides 1201-1203. In Table 4O, the start codon is in bold letters. Because the start and stop codons are not traditional initiation and termination codons, MOL4f could be a partial reading frame that extends further in the 5' and/or 3' directions.

Table 4O. MOL4f Nucleotide Sequence (SEQ ID NO:115).

GGATCCGGCCCATGGTCACCATGGCAACCATGTGAGCACTTGGATGGGGACAACTCAGGCTCTTGCCTGTGTCGA GCTCGATCCTGTGATTCCCCTCGACCCCGCTGTGGGGGCCTTGACTGCCTGGGGCCAGCCATCCACATCGCCAAC TGCTCCAGGAATGGGGCGTGGACCCCGTGGTCATCGTGGGCGCTGTGCAGCACGTCCTGTGGCATCGGCTTCCAG GTCCGCCAGCGAAGTTGCAGCAACCCTGCTCCCCGCCACGGGGGCCGCATCTGCGTGGGCAAGAGCCGGGAGGAA CGGTTCTGTAATGAGAACACGCCTTGCCCGGTGCCCATCTTCTGGGCTTCCTGGGGCTCCTGGAGCAAGTGCAGC AGCAACTGTGGAGGGGGCATGCAGTCGCGGCGTCGGGCCTGCGAGAACGGCAACTCCTGCCTGGGCTGCGGCGTG GAGTTCAAGACGTGCAACCCCGAGGGCTGCCCCGAAGTGCGGCGCAACACCCCCTGGACGCCGTGGCTGCCCGTG AACGTGACGCAGGGCGGGGCACGGCAGGAGCAGCGGTTCCGCTTCACCTGCCGCGCGCCCCTTGCAGACCCGCAC GGCCTGCAGTTCGGCAGGAGAAGGACCGAGACGAGGACCTGTCCCGCGGACGGCTCCGGCTCCTGCGACACCGAC GCCCTGGTGGAGGACCTCCTGCGCAGCGGGAGCACCTCCCCGCACACGGTGAGCGGGGGCTGGGCCGCCTGGGGC CCGTGGTCGTCCTGCTCCCGGGACTGCGAGCTGGGCTTCCGCGTCCGCAAGAGAACGTGCACTAACCCGGAGCCC CGCAACGGGGGCCTGCCCTGCGTGGGCGATGCTGCCGAGTACCAGGACTGCAACCCCCAGGCTTGCCCAGTTCGG GGTGCTTGGTCCTGCTGGACCTCATGGTCTCCATGCTCAGCTTCCTGTGGTGGGGGTCACTATCAACGCACCCGT TCCTGCACCAGCCCCGCACCCTCCCCAGGTGAGGACATCTGTCTCGGGCTGCACACGGAGGAGGCACTATGTGCC ACACAGGCCTGCCCAGAAGGCTGGTCGCCCTGGTCTGAGTGGAGTAAGTGCACTGACGACGGAGCCCAGAGCCGA AGCCGGCACTGTGAGGAGCTCCTCCCAGGGTCCAGCGCCTGTGCTGGAAACAGCAGCCAGAGCCGCCCCTGCGTC GAC

The 401 amino acid MOL4f polypeptide (SEQ ID NO: l 16) encoded by SEQ ID NO: 1 15 is presented using the one-letter amino acid code in Table 4P.

Table 4P. MOL4f protein sequence (SEQ ID NO:116)

GSGPWSPWQPCEHLDGDNSGSCLCRARSCDSPRPRCGGLDCLGPAIHIANCSRNGAWTPWSSWALCSTSCGIGFQV RQRSCSNPAPRHGGRICVGKSREERFCNENTPCPVPIFWASWGSWSKCSSNCGGGMQSRRRACENGNSCLGCGVEF KTCNPEGCPEVRRNTP TPWLPVNVTQGGARQEQRFRFTCRAPLADPHGLQFGRRRTETRTCPADGSGSCDTDALV EDLLRSGSTSPHTVSGGWAAWGP SSCSRDCELGFRVRKRTCTNPEPRNGGLPCVGDAAEYQDCNPQACPVRGAWS CWTS SPCSASCGGGHYQRTRSCTSPAPSPGEDICLGLHTEEALCATQACPEG SP SEWSKCTDDGAQSRSRHCE ELLPGSSACAGNSSQSRPCVD

MOL4g

The disclosed novel semaphorin-like protein, MOL4g (also referred to herein as 209829670), is encoded by a nucleic acid, 1203 nucleotides long (SEQ ID NOT 17). An open reading frame was identified beginning with an GGA initiation codon at nucleotides 1-3 and ending after a GAC codon at nucleotides 1201-1203. In Table 4Q, the start codon is in bold letters. Because the start and stop codons are not traditional initiation and termination codons, MOL4g could be a partial reading frame that extends further in the 5' and/or 3' directions. Table 4Q. MOL4g Nucleotide Sequence (SEQ ID NO:117).

GGATCCGGCCCATGGTCACCATGGCAACCATGTGAGCACTTGGATGGGGACAACTCAGGCTCTTGCCTGTGTCGA GCTCGATCCTGTGATTCCCCTCGACCCCGCTGTGGGGGCCTTGACTGCCTGGGGCCAACCATCCACATCGCCAAC TGCTCCAGGAATGGGGCGTGGACCCCGTGGTCATCGTGGGCGCTGTGCAGCACGTCCTGTGGCATCGGCTTCCAG GTCCGCCAGCGAAGTTGCAGCAACCCTGCTCCCCGCCACGGGGGCCGCATCTGCGTGGGCAAGAGCCGGGAGGAA CGGTTCTGTAATGAGAACACGCCTTGCCCGGTGCCCATCTTCTGGGCTTCCTGGGGCTCCTGGAGCAAGTGCGGC AGCAACTGTGGAGGGGGCATGCAGTCGCGGCGTCGGGCCTGCGAGAACGGCAACTCCTGCCTGGGCTGCGGCGTG GAGTTCAAGACGTGCAACCCCGAGGGCTGCCCCGAAGTGCGGCGCAACACCCCCTGGACGCCGTGGCTGCCCGTG AACGTGACGCAGGGCGGGGCACGGCAGGAGCAGCGGTTCCGCTTCACCTGCCGCGCGCCCCTTGCAGACCCGCAC GGCCTGCAGTTCGGCAGGAGAAGGACCGAGACGAGGACCTGTCCCGCGGACGGCTCCGGCTCCTGCGACACCGAC GCCCTGGTGGAGGTCCTCCTGCGCAGCGGGAGCACCTCCCCGCACACGGTGAGCGGGGGCTGGGCCGCCTGGGGC CCGTGGTCGTCCTGCTCCCGGGACTGCGAGCTGGGCTTCCGCGTCCGCAAGAGAACGTGCACTAACCCGGAGCCC CGCAACGGGGGCCTGCCCTGCGTGGGCGATGCTGCCGAGTACCAGGACTGCAACCCCCAGGCTTGCCCAGTTCGG GGTGCTTGGTCCTGCTGGACCTCATGGTCTCCATGCTCAGCTTCCTGTGGTGGGGGTCACTATCAACGCACCCGT TCCTGCACCAGCCCCGCACCCTCCCCAGGTGAGGACATCTGTCTCGGGCTGCACACGGAGGAGGCACTATGTGCC ACACAGGCCTGCCCAGAAGGCTGGTCGCCCTGGTCTGAGTGGAGTAAGTGCACTGACGACGGAGCCCAGAGCCGA AGCCGGCACTGTGAGGAGCTCCTCCCAGGGTCCAGCGCCTGTGCTGGAAACAGCAGCCAGAGCCGCCCCTGCGTC GAC

The 401 amino acid MOL4g polypeptide (SEQ ID NO: 118) encoded by SEQ ID NO:l 17 is presented using the one-letter amino acid code in Table 4R.

Table 4 . MOL4g protein sequence (SEQ ID NO: 118)

GSGPWSPWQPCEHLDGDNSGSCLCRARSCDSPRPRCGGLDCLGPTIHIANCSRNGAWTPWSSWALCSTSCGIGFQV RQRSCSNPAPRHGGRICVGKSREERFCNENTPCPVPIFWASWGSWSKCGSNCGGGMQSRRRACENGNSCLGCGVEF KTCNPEGCPEVRRNTP TP LPVNVTQGGARQEQRFRFTCRAPLADPHGLQFGRRRTETRTCPADGSGSCDTDALV EVLLRSGSTSPHTVSGGWAA GPWSSCSRDCELGFRVRKRTCTNPEPRNGGLPCVGDAAEYQDCNPQACPVRGA S C TS SPCSASCGGGHYQRTRSCTSPAPSPGEDICLGLHTEEALCATQACPEG SP SEWSKCTDDGAQSRSRHCE ELLPGSSACAGNSSQSRPCVD

Table 4S shows a ClustalW alignment ofthe MOL4 variants.

Table 4S. Clustal W for MOL4 variants

10 20 30 40 50 60 OL4a MPAGEGASAHRAGHHTRQARGGSRPSSRGMQGAPSRSSARLEAGGCSARRGRSAPAPSSF 60 MOL4b 1 OL4c 1

MOL4d 1

MOL4e 1

MOL4f 1 MOL4g ■ 1

70 80 90 100 110 120

MOL4a SLPLPSFSPFACNSSPTAPΞLLLLPRΞPPPCSLRAPGRELVGARGLVPEPSSAEPGGSAA 120 MOL4b 1

MOL4C 1

MOL4d 1

MOL4e 1 OL4f 1 MOL4g 1

130 140 150 160 170 180

MOL4a HPAAAGSPSAAGAGPGGDCTGALRAGGRSCAAAPFPDRPPAHLVSSRRSAPPGSREPRGT 180 MOL4b 1

MOL4c ■ ■ • 1

MOL4d 1

MOL4e 1 MOL4f 1

MOL4g 1

190 200 210 220 230 240

MOL4a GHLHPPLGVSGSSWCLACVS MPCGFSPSPVAHHLVPGPPDTPAQQLRCGWTVGG LLSL 240

MOL4b- --■ 1

MOL4C MPCGFSPSPVAHHLVPGPPDTPAQQLRCGWTVGGWLLSL 39

MOL4d 1 MOL4e 1 OL4f ^■ 1

MOL4g 1

250 260 270 280 290 300 OL4a VRGLLPCLPPGARTAEGPIMVLAGPLAVSLLLPSLTLLVSHLSSSQDVSSEPSSEQQLCA 300 OL4b MvLAGPLAVSLLLPSLTLLVSHLSSSQDVSSEPSSEQQLCA 41

MOL4C VRGLLPCLPPGARTAEGPIMVLAGPLAVSLLLPSLTLLVSHLSSSQDVSSEPSSEQQLCA 99

MOL4d 1 OL4e 1 OL4f 1

MOL4g ■ 1

310 320 330 340 350 360

MOL4a LSKHPTVAFEDLQPWVSNFTYPGARDFSQLALDPSGNQLIVGARNYLFRLSLANVΞLLQA 360

MOL4b LSKHPTVAFEDLQPWVSNFTYPGARDFSQLALDPSGNQLIVGARNYLFRLSLANVSLLQA 101

MOL4C LS HPTVAFEDLQP VSNFTYPGARDFSQLALDPSGNQLIVGARNYLFRLSLANVSLLQA 159

MOL4d 1 MOL4e 1

MOL4f 1

MOL4g > 1

370 380 390 400 410 420

MOL4a TEWASSEDTRRSCQSKGKTEEECQNYVRVLIVAGRKVFMCGTNAFSPMCTSRQVGNLSRT 420

MOL4b TE ASSEDTRRSCQSKGKTEEECQNYVRVLIVAGRKVFMCGTNAFSPMCTSRQVGNLSRT 161

MOL4C TEWASSEDTRRSCQSKGKTEEECQNYVRVLIVAGRKVFMCGTNAFSPMCTSRQVGNLSRT 219

MOL4d 1 MOL4e 1

MOL4f ■ 1

MOL4g 1

130 440 450 460 470 480

MOL4a TEKINGVARCPYDPRHNSTAVISSQGELYAATVIDFSGRDPAIYRSLGSGPPLRTAQYNS 480 OL4b TEKINGVARCPYDPRHNSTAVISSQGELYAATVIDFSGRDPAIYRSLGSGPPLRTAQYNS 221

MOL4C TEKINGVARCPYDPRH STAVISSQGELYAATVIDFSGRDPAIYRSLGSGPPLRTAQYNS 279 OL4d 1 MOL4e 1

MOL4f 1

MOL4g 1

490 500 510 520 530 540

MOL4a KWLNEPNFvAAYDIGLFAYFFLRENAVEHDCGRTVYSRVARVCKNDVGGRFLLEDTWTTF 540

MOL4b K LNEPNFVAAYDIGLFAYFFLRENAVEHDCGRTVYSRVARVCKNDVGGRFLLEDT TTF 281

MOL4C K LNEPNFVAAYDIGLFAYFFLRENAVEHDCGRTVYSRVARVCKNDVGGRFLLEDT TTF 339

MOL4d 1 MOL4e 1 OL4f 1 OL4g ■ 1

550 560 570 580 590 600

MOL4a MKARLNCSRPGEVPFYYNELQSAFHLPEQDLIYGVFTTNVNSIAASAVCAFNLSAISQAF 600 MOL4b MKARLNCSRPGEVPFYYNELQSAFHLPEQDLIYGVFTTNVNSIAASAVCAFNLSAISQAF 341 MOL4C MKARLNCSRPGEVPFYYNELQSAFHLPEQDLIYGVFTTNVNSIAASAVCAFNLSAISQAF 399 MOL4d OL4e OL4f OL4g

610 620 630 640 650 660

MOL4a NGPFRYQENPRAA LPIANPIPNFQCGTLPETGPNENLTERSLQDAQRLFLMSEAVQPVT 660 MOL4b NGPFRYQENPRAAWLPIANPIPNFQCGTLPETGPNENLTERSLQDAQRLFLMSEAVQPVT 401 OL4C NGPFRYQENPRAA LPIANPIPNFQCGTLPETGPNENLTERSLQDAQRLFLMSEAVQPVT 459

MOL4d MOL4e MOL4f MOL4g

670 680 690 700 710 720 OL4a PEPCVTQDSVRFSHLVVDLVQAKDTLYHVLYIGTESGTILKALSTASRSLHGCYLEELHV 720 OL4b PEPCVTQDSVRFSHLWDLVQAKDTLYHVLYIGTESGTILKALSTASRSLHGCYLEELHV 461 OL4C PEPCVTQDSVRFSHLWDLVQAKDTLYHVLYIGTESGTILKALSTASRSLHGCYLEELHV 519 OL4d MOL4e MOL4f MOL4g

730 740 750 760 770 780 OL4a LPPGRREPLRSLRILHSARALFVGLRDGVLRVPLERCAAYRSQGACLGARDPYCG DGKQ 780 MOL4b LPPGRREPLRSLRILHSARALFVGLRDGVLRVPLERCAAYRSQGACLGARDPYCG DGKQ 521 MOL4C LPPGRREPLRSLRILHSARALFVGLRDGVLRVPLERCAAYRSQGACLGARDPYCGWDGKQ 579 OL4d MOL4e MOL4f MOL4g

790 800 810 820 330 10 OL4a QRCSXLEDSSNMSLWTQNITACPVRNVTRDGIgF 840 OL4b QRCSTLEDSSNMSLWTQNITACPVRNVTRDi PWSPWQBCEHLDGDNSGSCLCRARS 581

MOL4C QRCSTLEDSSNMSLWTQNITACPVRNVT: PWSPWQPCEHLDGDNSGSCLCRARS 639 OL4d @S jP SPWQPCEHLfiGDKfέJ3SC CRAR^'S 29 OL4e JPWSPWQPCEHLDGDNSGSCLCRARS 29

MOL4f JPWSPWQPCEHLDGDNSGSCLCRARS 29

MOL4g WSPWQPCEHLDGDNSGSCLCRARS 29

850 860 870 880 390 900 OL4a naaaaaytfrtBiW-rrtsfeWiwa MOL4b SPRPRCGGLDCLGPAIHIANCSR GAWTPWSSWALCSTSCGIGFQVRQRSCSNPAPRΞ MOL4c SPRPRCGGLDCLGPAIHIANCSRNGAWTPWSSWALCSTSCGIGFQVRQRSCSNPAPRH OL4d SPRPRCGGLDCLGPAIHIANCSRNGAWTP SSWALCSTSCGIGFQTOQRSCSNPAPRH OL4e SPRPRCGGLDCLGPAIHIANCSRNGAWTPWSSWALCSTSCGIGFQVRQRSCSNPAPRHI. MOL4f SPRPRCGGLDCLGPAIHIANCSR GAWTPWSSWALCSTSCGIGFQVRQRSCSNPAPRHC MOL4g SPRPRGGGLDCLGPBIHIANCSRNGAWTPWSSWALCSTSCGIGFQVRQRSCSNPAPRH

910 920 930 940 950 960

MOL4a ICVGKSREERFCNENTPCPVPIFWASWGSWS CSSNCGGGMQSRRRACENGNSCLGCG MOL4b RICVGKSREERFCNENTPCPVPIFWASWGSWSKCSSNCGGGMQSRRRACENGNSCLGCG MOL4C RICVGKSREERFCNENTPCPVPIFWASWGSWS CSSNCGGGMQSRRRACENGNSCLGCG OL4d JRICVGKSREERFCNENTPCPVPIFWASWGSWS CSSNCGGGMUSRRRACENGNSCLGCG OL4e "RICVGKSREERFCNENTPCPVPIFWASWGSWS CSSNCGGGMQSRRRACENGNSCLGCG OL4f .RICVG SREERFCNENTPCPVP1FWASWGSWSKCSSNCGGG QSRRRACENGNSCLGCG MOL4g ICVG SREERFCNENTPCPVPIFWASWGSWS CSSNCGGGMQSRRRACENGNSCLGCG

970 980 990 1000 1010 1020

I

MOL4a aaw! mraeiaaaϋ 1020 MOL4b nftrt-.. ni >.. nil i/ai -**«■ tftAkl Λ* MriM -lι i 761 MOL4C TFEFKTCNPEGCPEVRRNTPWTPWLPVNVTQGGARQ. IQRFRFTCRAPLADPHGLQFGRRR 819 OL4d TEFKTCNPEGCPEVRRNTPWTPWLPVNVTQGGARQ: IQRFRFTCRAPLADPHGLQFGRRR 209 MOL4e \7EFKTCNPEGCPEVRRNTPWTPWLPVNVTQGGARQ: IQRFRFTCRAPLADPHGLQFGRRR'J 209 OL4f S/EF TCNPEGCPEVRRNTPWTPWLPVNVTQGGARQ: IQRFRFTCRAPLADPHGLQFGRFJM 209 MOL4g 7EFKTCNPEGCPEVRRNTPWTPWLPVNVTQGGARQ IQRFRFTCRAPLADPHGLQFGRRR' 209

1030 1040 1050 1060 1070 1080

ETRTCPADGSGSCDTDALVEDLLRSGSTSPHTVSGGWAAWGPWSSCSRDCELGFRVRKR': ETRTCPADGSGSCDTDALVEDLLRSGSTSPHTVSGGWAAWGPWSSCSRDCELGFRVR ETRTCPADGSGSCDTDALVEDLLRSGSTSPHTVSGGWAAWGPWSSCSRDCELGFRVRKR ETRTCPADGSGSCDTDALVEDLLRSGSTSPHTVSGGWAAWGPWSSCSRDCELGFRVRKR ETRTCPADGSGSCDTDALVEDLLRSGSTSPHTVSGGWAAWGPWSSCSRDCELGFRVRKR

ETRTCPADGSGSCDTDALVEDLLRSGSTSPHTVSGGWAAWGPWSSCSRDCELGFRVRKRJ

ETRTCPADGSGSCDTDALVEBLLRSGSTSPHTVSGGWAAWGPWSSCSRDCELGFRVRKR

1090 1100 1110 1120 1130 1140

TNPEPRNGGLPCVGDAAEYQDCNPQACPVRGAWSCWTSWSPCSASCGGGHYQRTRSCTS ^"■.TNPEPRNGGLPCVGDAAEYQDCNPQACPVRGAWSCWTSWSPCSASCGGGHYQRTRSCTS

:TNPEPRNGGLPCVGDAAEYQDCNPQACPVRGAWSCWTSWSPCSASCGGGHYQRTRSCTS :TNPE||RNGGLPCVGDAAEYQDCNPQACPVRGAWSCWTSWSPCSASCGGGHYQRTRSCTS

,'TTIPEPRNGGLPCVGDAAEYQDCNPQACPVRGAWSCWTSWSPCSASCGGGHYQRTRSCTS

ITNPEPRNGGLPCVGDAAEYQDCNPQACPVRGAWSCWTSWSPCSASCGGGHYQRTRSCTS

1150 1160 1170 1180 1190 1200

1210 1220 1230 1240 1250 1260

1270 1280 1290 1300 1310 1320 OL4a QHCQRQSQESTLVHPATPNHLHYKGGGTPKNEKYTPMEFKTLNKNNLIPDDRANFYPLQQ 1320 OL4b QHCQRQSQESTLVHPATPNHLHYKGGGTPKNEKYTPMEFKTLNKNNLIPDDRANFYPLQQ 1061

MOL4C QHCQRQSQESTLVHPATPNHLHYKGGGTPKNEKYTPMEF TLNKNNLIPDDRANFYPLQQ 1098 OL4d 401 OL4e 401

MOL4f • 401

MOL4g 401

1330 1340 1350 OL4a TNVYTTTYYPSPLNKHSFRPEASPGQRCFPNS 1352

MOL4b TNVYTTTYYPSPLNKHSFRPEASPGQRCFPNS 1093

MOL4C TNVYTTTYYPSPLNKHSFRPEASPGQRCFPNS 1130 OL4d 401 OL4e 401

MOL4f 401

MOL4g 401 MOL4a has homology to the proteins decribed in Table 4T.

This information is presented graphically in the multiple sequence alignment given in Table 4U (with MOL4 being shown on line 1) as a ClustalW analysis comparing MOL4 with related sequences. Table 4U Information for the ClustalW proteins:

1) MOL4 (SEQ ID NO: 12)

2) gi I 12731706 I ref |XP_004042.2 I sema domain, seven thrombospondin repeats (type 1 and type 1-like) , transmembrane domain (TM) and short cytoplasmic domain, (semaphorin) 5A [Homo sapiens] (SEQ ID NO: 41)

3) gi ] 7305473 I ref |NP_038689.11 sema domain, seven thrombospondin repeats (type 1 and type 1-like) , transmembrane domain (TM) and short cytoplasmic domain, (sem [Mus musculus] (SEQ ID NO:42)

4) gi I 6677915 |ref |NP_033180.11 sema domain, seven thrombospondin repeats (type 1 and type 1-like) , transmembrane domain (TM) and short cytoplasmic domain, (sem,- M-Sema D [Mus musculus] (SEQ ID NO: 43)

5) gi I 45068811 ref |NP_003957.1 ] sema domain, seven thrombospondin repeats (type 1 and type 1-like) , transmembrane domain (TM) and short cytoplasmic domain, (semaphorin) 5A,- semaphorin F; sema domain, seven thrombospondin repeats (type 1 and type 1-like), transmembrane domain (TM) (SEQ ID NO:44)

6) gi I 7959149 |dbj |BAA95969.l| (AB040878) KIAA1445 protein [Homo sapiens] (SEQ ID NO: 45)

10 20 30 50

MOL4 MPAGEGASAHRAGHHTRQARGGSRPSSRGMQGAPS SSARLEAGGCSARR gi|l2731706| gi|7305473] gi|6677915| gi|4S0688l| gi]7959149|

60 70 80 90 100 GRSAPAPSSFSLPLPSFSPFACNSSPTAPSLLLLPRSPPPCSLRAPGREL

110 120 130 140 150

MOL4 VGARGLVPEPSSAEPGGSAAHPAAAGSPSAAGAGPGGDCTGALRAGGRSC

160 170 180 190 200 ..|..

MOL4 AAAPFPDRPPAHLVSSRRSAPPGSREPRGTGHLHPPLGVSGSSWCIACVS

AAAPFPDRPPAHLVSSRRSAPPGSREPRGTGHLHPPLGVSGSS CLACVS 210 220 230 240 250

....|....|....|....|....]....]....|....|....|....|

MOL4 WMPCGFSPSPVAHHLVPGPPDTPAQQLRCGWTVGGWLLSLVRGLLPCLPP gi|l2731706| gi]7305473| gi]6677915] gi]450688l] gi|7959149J MPCGFSPSPVAHHLVPGPPDTPAQQLRCGWTVGGWLLSLVRGLLPCLPP

gi | 7959149 | GARTAEGPIMVLASPLAVSLSJLPSJTHLVSHLSSSQDVSSEPSSEQQLSA

710 720 730 750

I----I ^■I----I

1360

M0L4 ASPGQRCFPNS

ASPGQRCFPNS

ASPGQRCFPNS

Tables 4V-4AA list the domain descriptions from DOMAIN analysis results against MOL4a. The region from amino acid residue 327 through 725 (SEQ ID NO: 12) most probably (E = 2e^{"1 18}) contains a Sema domain found in Semaphorins, aligned here in Table 4V. Semaphorins are involved in growth cone guidance, axonal pathfmding, and other developmental processes. The region from amino acid residue 1057 through 1109 (SEQ ID NO: 12) most probably (E = 3e^"9) contains a Thrombospondin type-1 repeat found in thrombospondin- 1 that binds to and activates TGF-beta, aligned here in Table 4W. TGF-beta is involved in the modulation of proliferation in many cell types. The region from amino acid residue 868 through 921 (SEQ ID NO:12) most probably (E = 4e^~8) also contains a Thrombospondin type-1 repeat found in thrombospondin- 1 that binds to and activates TGF-beta, aligned here in Table AX. The region from amino acid residue 926 through 972 (SEQ ID NO: 12) most probably (E = 6e^"7) also contains a Thrombospondin type-1 repeat found in thrombospondin- 1 that binds to and activates TGF-beta, aligned here in Table 4Y. The region from amino acid residue 1 169 through 1210 (SEQ ID NO: 12) most probably (E = 0.001) also contains a Thrombospondin type-1 repeat found in thrombospondin- 1 that binds to and activates TGF-beta, aligned here in Table AZ. The region from amino acid residue 756 through 803 (SEQ ID NO:12) most probably (E = le^{" 5}) also contains a Thrombospondin type-1 repeat found in thrombospondin-1 that binds to and activates TGF-beta, aligned here in Table 4AA. The presence of these domains indicates that the MOL4a sequence has properties similar to those of other proteins known to contain these domains.

70 80 90 0L4a_l II -VAG-RKVFMB |SgMWTSRQV

Smart I smart00630 jJLHLDYNA-DRLLvB aQHVlRLINL

- SϋfflvLB

410 420 430 440 450

MOL4a_l FSHL ,VvIffifflL-ffi SQQ- -AKDTLHHH ISJSiESBTl STA|Rg-L H

Smart | smart00630 LTSI. ER-BR- -TDGGNHTHJF: ^SD| LSEBSHSS E

460 470

(SEQ ID NO : 91)

Table 4W. Domain Analysis of MOL4a gnl 1 Smart | smart00209 , TSPl, Thrombospondin type 1 repeats,- Type 1 repeats in thrombospondin- 1 bind and activate TGF-beta. CD-Length = 51 residues, 100.0% aligned Score = 58.2 bits (139), Expect = 3e-09

MOL4a_3 Smar | smart

(SEQ ID NO : 92 )

Table 4X. Domain Analysis of MOL4a gnl j Smart | smart00209, TSPl, Thrombospondin type 1 repeats,- Type 1 repeats in thrombospondin- 1 bind and activate TGF-beta. CD-Length = 51 residues, 100.0% aligned Score = 54.3 bits (129), Expect = 4e-08

30 40 50

M0L4a 4

Smart smart00209

MOL4a_4

Smart I smart00209 (SEQ ID NO : 93 )

60

M0L4a_5 aEALB

Smart I smart 00209 STRAB (SEQ ID NO : 94 )

Table 4Z. Domain Analysis of MOL4a gnl 1 Smart ] smart00209, TSPl, Thrombospondin type 1 repeats; Type 1 repeats in thrombospondin- 1 bind and activate TGF-beta. CD-Length = 51 residues, 88.2% aligned Score = 39.7 bits (91), Expect = 0.001

10 20 30 40 50

MOL4a 6 |2J SiJiGsE_ijκ|3i]SN| @SSR1- g E- -N@NS@ScG |gFK;τg Smart | smart00209 EGEEsE|ϊSPEEa^vτE-S-^vSτiϊl^τiϊl-C_S^NPPPN- -G@GPS SPDτ τRASS]

(SEQ ID NO: 95)

Table 4AA. Domain Analysis of MOL4a gnl ] Pfam]pfam01437, Plexin_repeat, Plexin repeat

CD-Length = 48 residues, 100.0% aligned

Score = 46.2 bits (108), Expect = le-05

10 20 30 40 50

MOL4a_8 RfflAAY-RSQGAffl GgRJ3-5 ^^DGKQQ^SτBraDsΘ MS LBBTB

Pfam | pfam01437 "SOH-T"CSSBIIS" '-"G!^ICPSRKISBITRB^EC"RGE G^Sg

MOL4a_8 NITAS Pfam | pfam01437 SSETB (SEQ ID NO : 96 )

The above defined information for MOL4 suggests that this semaphorin-like protein may function as a member of a "Semaphorin family". Therefore, the novel nucleic acids and proteins identified here may be useful in potential therapeutic applications implicated in (but not limited to) various pathologies and disorders as indicated below. The potential therapeutic applications for MOL4 include, but are not limited to: protein therapeutic, small molecule drug target, antibody target (therapeutic, diagnostic, drug targeting/cytotoxic antibody), diagnostic and/or prognostic marker, gene therapy (gene delivery/gene ablation), research tools, tissue regeneration in vivo and in vitro of all tissues and cell types composing (but not limited to) those defined here.

The thrombospondin type 1 repeat (TSR) superfamily: diverse proteins with related roles in neuronal development.

Adams JC, Tucker RP. Dev Dyn 2000 Jun;218(2):280-99 The semaphorins are a gene family characterized by the presence of a phylogenetically conserved 500-amino acid domain (Kolodkin et al., [1993]). Some are secreted, some are associated with the cell surface via a GPI linkage, and others are transmembrane proteins. Many are expressed in the developing nervous system, and at least some of these have repulsive properties (e.g., Raper and Kapfliammer, [1990]; Luo et al, [1993]; Pueschel et al., [1995]). Adams et al. ([1996]) cloned two novel semaphorins from murine cDNA libraries that they designated SemF and SemG. SemF and SemG are 72% similar to each other and share a common domain organization: a relatively short cytoplasmic tail with proline-rich SH3 domains (analyzed further by Wang et al., [1999]), a single hydrophobic transmembrane domain, seven TSRs that contain WSXW motifs but lack the CSVTCG motif, and finally the large semaphorin domain. Northern blotting revealed semG expression in the early (El l) mouse embryo, when in situ hybridization showed semG expression in the neuroepithelium (Adams et al., [1996]; Skaliora et al., [1998]). Thus, SemG could play a role in neuroblast proliferation. In the adult, SemG mRNA was detected in brain but not in any other tissue examined (Adams et al., [1996]). Adams RH, Betz H, Puschel AW. 1996. A novel class of murine semaphorins with homology to thrombospondin is differentially expressed during early embryogenesis. Mech Dev 57: 33-45.

Skaliora I, Singer W, Betz H, Puschel AW. 1998. Differential patterns of semaphorin expression in the developing rat brain. Eur Neurosci 10: 1215-1229. The MOL4 nucleic acids and proteins are useful in potential therapeutic applications implicated in Parkinson's disease, psychotic and neurological disorders, Alzheimers disease, cancer including but not limited to lung or breast cancer, endocrine disorders, inflammatory disorders, gastro-intestinal disorders and disorders ofthe respiratory system, and/or other pathologies and disorders. For example, a cDNA encoding the semaphorin-like protein may be useful in gene therapy, and the semaphorin-like protein may be useful when administered to a subject in need thereof. By way of nonlimiting example, the compositions ofthe present invention will have efficacy for treatment of patients suffering from Parkinson's disease, psychotic and neurological disorders, Alzheimers disease, cancer including but not limited to lung or breast cancer, endocrine disorders, inflammatory disorders, gastro-intestinal disorders and disorders of he respiratory system. MOL4, or fragments thereof, may further be useful in diagnostic applications, wherein the presence or amount ofthe nucleic acid or the protein are to be assessed.

These materials are further useful in the generation of antibodies that bind immuno-specifically to the novel MOL4 substances for use in therapeutic or diagnostic methods. These antibodies may be generated according to methods known in the art, using prediction from hydrophobicity charts, as described in the "Anti-MOLX Antibodies" section below. The disclosed MOL4 protein has multiple hydrophilic regions, each of which can be used as an immunogen. In one embodiment, a contemplated MOL4 epitope is from about amino acids 5 to 75. In another embodiment, a MOL4 epitope is from about amino acids 100 to 200. n additional embodiments, MOL4 epitopes are from about amino acids 300 to 375, 420 to 600, 600 to 675, 775 to 850, 900 to 1 150, , and from about amino acids 1250 to 1350. These novel proteins can also be used to develop assay systems for functional analysis. MOL5

MOL5a

The disclosed novel semaphorin 4C -like nucleic acid of 3868 nucleotides, MOL5a, (also referred to as SC20422974-A) is shown in Table 5A. An ORF begins with an ATG initiation codon at nucleotides 453-455 and ends with a TGA codon at nucleotides 2952-2954. A putative untranslated region upstream from the initiation codon and downstream from the termination codon is underlined in Table 5A, and the start and stop codons are in bold letters.

Table 5A. MOL5a Nucleotide Sequence (SEQ ID NO:13)

CGACTATCCATGAAGCCCGGAGCCCCAGTGGCTGCAAGGCCTGCTGCCTGAGGTTCTTTCAAGAAACTCAAACCT CTTAGGCCTGAGTGTGTATGTTGGGCGGGGGTCCCCTTTTTATTTCTCAAATGATTTCCTGTTGCGCAGAGGTAG TGGTGGGTCTGGAGGCCAGGGAGGGCTTCCCGGAGCCTGTTTAGCCTTCAGCCAACTCAACTCCTCCCCGCTTCC CAGGGAGACCTGTGGTCTTTTAGGCAGAGGCCAAGTGTGGGGACTTAGGTCCACCTCCAAAGAGAAGGGGAAGGA GGGCACCGGGGCTCCTGGAAGGCCTGATGAGGAGTCCTGTGGCCTCTCCTGCTGCGGGCCCCTCTGGTTTGCTTT CTCTGGCTGTGATTTCTGACCATGTCTTTTCCCTCAGCAGGACAGCTGGCCTGAAGCTCAGAGCCGGGGCGTGCG CCATGGCCCCACACTGGGCTGTCTGGCTGCTGGCAGCAAGGCTGTGGGGCCTGGGCATTGGGGCTGAGGTGTGGT GGAACCTTGTGCCGCGTAAGACAGTGTCTTCTGGGGAGCTGGCCACGGTAGTACGGCGGTTCTCCCAGACCGGCA TCCAGGACTTCCTGACACTGACGCTGACGGAGCCCACTGGGCTTCTGTACGTGGGCGCCCGAGAGGCGCTGTTTG CCTTCAGTGTAGAGGCTCTGGAGCTGCAAGGAGCGATCTCCTGGGAGGCCCCCGTGGAGAAGAAGACTGAGTGTA TCCAGAAAGGGAAGAACAACCAGACCGAGTGCTTCAACTTCATCCGCTTCCTGCAGCCCTACAATGCCTCCCACC TGTACGTCTGTGGCACCTACGCCTTCCAGCCCAAGTGCACCTACGTCAACATGCTCACCTTCACTTTGGAGCATG GAGAGTTTGAAGATGGGAAGGGCAAGTGTCCCTATGACCCAGCTAAGGGCCATGCTGGCCTTCTTGTGGATGGTG AGCTGTACTCGGCCACACTCAACAACTTCCTGGGCACGGAACCCATTATCCTGCGTAACATGGGGCCCCACCACT CCATGAAGACAGAGTACCTGGCCTTTTGGCTCAACGAACCTCACTTTGTAGGCTCTGCCTATGTACCTGAGAGTG TGGGCAGCTTCACGGGGGACGACGACAAGGTCTACTTCCTCTTCAGGGAGCGGGCAGTGGAGTCCGCCTGCTATG CCGAGCAGGTGGTGGCTCGTGTGGCCCGTGTCTGCAAGGGCGATATGGGGGGCGCACGGACCCTGCAGAGGAAGT GGACCACGTTCCTGAAGGCGCGGCTGGCATGCTCTGCCCCGAACTGGCAGCTCTACTTCAACCAGCTGCAGGCGA TGCACACCCTGCAGGACACCTCCTGGCACAACACCACCTTCTTTGGGGTTTTTCAAGCACAGTGGGGTGACATGT ACCTGTCGGCCATCTGTGAGTACCAGTTGGAAGAGATCCAGCGGGTGTTTGAGGGCCCCTATAAGGAGTACCATG AGGAAGCCCAGAAGTGGGACCGCTACACTGACCCTGTACCCAGCCCTCGGCCTGGCTCGTGCATTAACAACTGGC ATCGGCGCCACGGCTACACCAGCTCCCTGGAGCTACCCGACAACATCCTCAACTTCGTCAAGAAGCACCCGCTGA TGGAGGAGCAGGTGGGGCCTCGGTGGAGCCGCCCCCTGCTCGTGAAGAAGGGCACCAACTTCACCCACCTGGTGG CCGACCGGGTTACAGGACTTGATGGAGCCACCTATACAGTGCTGTTCATTGGCACAGGTCAGGCATGGCTGCTCA AGGCTGTGAGCCTGGGGCCCTGGGTTCACCTGATTGAGGAGCTGCAGCTGTTTGACCAGGAGCCCATGAGAAGCC TGGTGCTATCTCAGTCGCAGAAGCTGCTCTTTGCCGGCTCCCGCTCTCAGCTGGTGCAGCTGCCCGTGGCCGACT GCATGAAGTATCGCTCCTGTGCAGACTGTGTCCTCGCCCGGGACCCCTATTGCGCCTGGAGCGTCAACACCAGCC GCTGTGTGGCCGTGGGTGGCCACTCTGGGTCCTTTCTGATCCAGCATGTGATGACCTCGGACACTTCAGGCATCT GCAACCTCCGTGGCAGTAAGAAAGTCAGGCCCACTCCCAAAAACATCACGGTGGTGGCGGGCACAGACCTGGTGC TGCCCTGCCACCTCTCCTCCAACTTGGCCCATGCCCGCTGGACCTTTGGGGGCCGGGACCTGCCTGCGGAACAGC CCGGGTCCTTCCTCTACGATGCCCGGCTCCAGGCCCTGGTTGTGATGGCTGCCCAGCCCCGCCATGCCGGGGCCT ACCACTGCTTTTCAGAGGAGCAGGGGGCGCGGCTGGCTGCTGAAGGCTACCTTGTGGCTGTCGTGGCAGGCCCGT CGGTGACCTTGGAGGCCCGGGCCCCCCTGGAAAACCTGGGGCTGGTGTGGCTGGCGGTGGTGGCCCTGGGGGCTG TGTGCCTGGTGCTGCTGCTGCTGGTGCTGTCATTGCGCCGGCGGCTGCGGGAAGAGCTGGAGAAAGGGGCCAAGG CTACTGAGAGGACCTTGGTGTACCCCCTGGAGCTGCCCAAGGAGCCCACCAGTCCCCCCTTCCGGCCCTGTCCTG AACCAGATGAGAAACTTTGGGATCCTGTCGGTTACTACTATTCAGATGGCTCCCTTAAGATAGTACCTGGGCATG CCCGGTGCCAGCCCGGTGGGGGGCCCCCTTCGCCACCTCCAGGCATCCCAGGCCAGCCTCTGCCTTCTCCAACTC GGCTTCACCTGGGGGGTGGGCGGAACTCAAATGCCAATGGTTACGTGCGCTTACAACTAGGAGGGGAGGACCGGG GAGGGCTCGGGCACCCCCTGCCTGAGCTCGCGGATGAACTGAGACGCAAACTGCAGCAACGCCAGCCACTGCCCG ACTCCAACCCCGAGGAGTCATCAGTATGAGGGGAACCCCCACCGCGTCGGCGGGAAGCGTGGGAGGTGTAGCTCC TACTTTTGCACAGGCACCAGCTATCTCAGGGACATGGCACGGGCACCTGCTCTGTCTGGGACAGATACTGCCCAG CACCCACCCGGCCATGAGGACCTGCTCTGCTCAGCACGGGCACTGCCACTTGGTGTGGCTCACCAGGGCACCAGC CTCGCAGAAGGCATCTTCCTCCTCTCTGTGAATCACAGACACGCGGGACCCCAGCCGCCAAAACTTTTCAAGGCA GAAGTTTCAAGATGTGTGTTTGTCTGTATTTGCACATGTGTTTGTGTGTGTGTGTATGTGTGTGTGCACGCGCGT GCGCGCTTGTGGCATAGCTTCCTGTTTCTGTCAAGTCTTCCCTTGGCCTGGGTCCTCCTGGTGAGTCATTGGAGC TATGAAGGGGAAGGGGTCGTATCACTTTGTCTCTCCTACCCCCACTGCCCCGAGTGTCGGGCAGCGATGTACATA TGGAGGTGGGGTGGACAGGGTGCTGTGCCCCTTCAGAGGGAGTGCAGGGCTTGGGGTGGGCCTAGTCCTGCTCCT AGGGCTGTGAATGTTTTCAGGGTGGGGGGAGGGAGATGGAGCCTCCTGTGTGTTTGGGGGGAAGGGTGGGTGGGG CCTCCCACTTGGCCCCGGGGTTCAGTGGTATTTTATACTTGCCTTCTTCCTGTACAGGGCTGGGAAAGGCTGTGT GAGGGGAGAGAAGGGAGAGGGTGGGCCTGCTGTGGACAATGGCATACTCTCTTCCAGCCCTAGGAGGAGGGCTCC TAACAGTGTAACTTATTGTGTCCCCGCGTATTTATTTGTTGTAAATATTTGAGTATTTTTATATTGACAAATAAA ATGGAGAAAAAAAAAAAAAAAAAAAAAAAAGTCGTATCGATGT

The MOL5a protein encoded by SEQ ID NO: 13 has 833 amino acid residues and is presented using the one-letter code in Table 5B. The Psort profile for MOL5a predicts that this sequence is likely to be localized at the mitochondrial inner membrane with a certainty of 0.8000 or plasma membrane with a certainty of 0.7000. MOL5a has a cleavage site between amino acods 20 and 21 (GIG-AE), and a molecular weight of 92617.0 Daltons.

Table 5B. Encoded MOL5a protein sequence (SEQ ID NO:14)

MAPHWAVWLLAARLWGLGIGAEVWWNLVPRKTVSSGELATVVRRFSQTGIQDFLTLTLTEPTGLLYVGAREAL FAFSVEALELQGAISWEAPVEKKTECIQKGKE QTECFNFIRFLQPYNASHLYVCGTYAFQPKCTYVNMLTFT LEHGEFEDGKGKCPYDPA GHAGLLVDGELYSATLNNFLGTEPIILRNMGPHHSMKTEYLAF LNEPHFVGSA YVPESVGSFTGDDD VYFLFRERAVESDCYAEQWARVARVCKGDMGGARTLQRKWTTFLKARLACSAPNWQL YFNQLQAMHTLQDTS HNTTFFGVFQAQWGDMYLSAICEYQLEEIQRVFEGPYKEYHEEAQKWDRYTDPVPSP RPGSCIN HRRHGYTSSLELPDNILNFVKKHPLMEEQVGPR SRPLLVKKGTNFTHLVADRVTGLDGATYTV LFIGTGQAWLLKAVSLGPWVHLIEELQLFDQEPMRSLVLSQSQKLLFAGSRSQLVQLPVADCMKYRSCADCVL ARDPYCA SVMTSRCVAVGGHSGSFLIQHVMTSDTSGICNLRGSKKVRPTPK ITWAGTDLVLPCHLSSWLA HARWTFGGRDLPAEQPGSFLYDARLQALWMAAQPRHAGAYHCFSEEQGARLAAEGYLVAWAGPSVTLEARA PLENLGLVWLAVVALGAVCLVLLLLVLSLRRRLREELEKGAKATERTLVYPLELPKEPTSPPFRPCPEPDEKL DPVGYYYSDGSLKIVPGHARCQPGGGPPSPPPGIPGQPLPSPTRLHLGGGRNSNANGYVRLQLGGEDRGGLG HPLPELADELRRKLQQRQPLPDSNPEESSV

The disclosed nucleic acid sequence for MOL5a has 2917 of 3443 bases ( 84%) identical to a semaphorin 4C mRNA (GENBANK-ID: S79463|acc:S79463 ) (E= 0.0).

The full MOL5a amino acid sequence has 729 of 834 amino acid residues (87%) identical to, and 772 of 834 residues (92%) positives with, the 834 amino acid semaphorin 4C Precursor protein from Mus musculus (Mouse) (ptnr:SPTREMBL-ACC: Q64151) (E= 0.0). In addition, this protein contains the following protein domains (as defined by

Interpro) at the indicated nucleotide positions: Sema domain (a.a. 53-481; IPR001627), integrinJB (a.a. 505-519; IPR000413 ), Plexinjrepeat (a.a. 499-551; IPR002165), ig (a.a. 570-629; IPR000353)

MOL5a expression in different tissues was examined through TaqMan as described below in Example 1.

Chromosomal Localization MOL5a has been localized to human chromosome 2. MOL5b

Another disclosed novel semaphorin 4C -like nucleic acid of 2558 nucleotides, MOL5b, (also referred to as SC14998905_EXT) is shown in Table 5C. An ORF begins with an ATG initiation codon at nucleotides 21 - 23 and ends with a TGA codon at nucleotides 2520-2522. A putative untranslated region upstream from the initiation codon and downstream from the termination codon is underlined in Table 5C, and the start and stop codons are in bold letters.

Table 5C. MOL5b Nucleotide Sequence (SEQ ID NO: 15)

TCAGAGCCGGGGCGTGCGCCATGGCCCCACACTGGGCTGTCTGGCTGCTGGCAGCAAGGCTGTGGGGCCTGGGCA TTGGGGCTGAGGTGTGGTGGAACCTTGTGCCGCGTAAGACAGTGTCTTCTGGGGAGCTGGCCACGGTAGTACGGC GGTTCTCCCAGACCGGCATCCAGGACTTCCTGACACTGACGCTGACGGAGCCCACTGGGCTTCTGTACGTGGGCG CCAGGGACCATGCCTCTGCACTGGGCGTCCCTGTGTTGCTGCTGCAGGCTGTGATCTCCTGGGAGGCCCCCGTGG AGAAGAAGACTGAGTGTATCCAGAAAGGGAAGAACAACCAGACCGAGTGCTTCAACTTCATCCGCTTCCTGCAGC CCTACAATGCCTCCCACCTGTACGTCTGTGGCACCTACGCCTTCCAGCCCAAGTGCACCTACGTCAACATGCTCA CCTTCACTTTGGAGCATGGAGAGTTTGAAGATGGGAAGGGCAAGTGTCCCTATGACCCAGCTAAGGGCCATGCTG GCCTTCTTGTGGATGGTGAGCTGTACTCGGCCACACTCAACAACTTCCTGGGCACGGAACCCATTATCCTGCGTA ACATGGGGCCCCACCACTCCATGAAGACAGAGTACCTGGCCTTTTGGCTCAACGAACCTCACTTTGTAGGCTCTG CCTATGTACCTGAGAGTGTGGGCAGCTTCACGGGGGACGACGACAAGGTCTACTTCTTCTTCAGGGAGCGGGCAG TGGAGTCCGACTGCTATGCCGAGCAGGTGGTGGCTCGTGTGGCCCGTGTCTGCAAGGGCGATATGGGGGGCGCAC GGACCCTGCAGAGGAAGTGGACCACGTTCCTGAAGGCGCGGCTGGCATGCTCTGCCCCGAACTGGCAGCTCTACT TCAACCAGCTGCAGGCGATGCACACCCTGCAGGACACCTCCTGGCACAACACCACCTTCTTTGGGGTTTTTCAAG CACAGTGGGGTGACATGTACCTGTCGGCCATCTGTGAGTACCAGTTGGAAGAGATCCAGCGGGTGTTTGAGGGCC CCTATAAGGAGTACCATGAGGAAGCCCAGAAGTGGGACCGCTACACTGACCCTGTACCCAGCCCTCGGCCTGGCT CGTGCATTAACAACTGGCATCGGCGCCACGGCTACACCAGCTCCCTGGAGCTACCCGACAACATCCTCAACTTCG TCAAGAAGCACCCGCTGATGGAGGAGCAGGTGGGGCCTCGGTGGAGCCGCCCCCTGCTCGTGAAGAAGGGCACCA ACTTCACCCACCTGGTGGCCGACCGGGTTACAGGACTTGATGGAGCCACCTATACAGTGCTGTTCATTGGCACAG GAGACGGCTGGCTGCTCAAGGCTGTGAGCCTGGGGCCCTGGGTTCACCTGATTGAGGAGCTGCAGCTGTTTGACC AGGAGCCCATGAGAAGCCTGGTGCTATCTCAGAGCAAGAAGCTGCTCTTTGCCGGCTCCCGCTCTCAGCTGGTGC AGCTGCCCGTGGCCGACTGCATGAAGTATCGCTCCTGTGCAGACTGTGTCCTCGCCCGGGACCCCTATTGCGCCT GGAGCGTCAACACCAGCCGCTGTGTGGCCGTGGGTGGCCACTCTGGATCTCTACTGATCCAGCATGTGATGACCT CGGACACTTCAGGCATCTGCAACCTCCGTGGCAGTAAGAAAGTCAGGCCCACTCCCAAAAACATCACGGTGGTGG CGGGCACAGACCTGGTGCTGCCCTGCCACCTCTCCTCCAACTTGGCCCATGCCCGCTGGACCTTTGGGGGCCGGG ACCTGCCTGCGGAACAGCCCGGGTCCTTCCTCTACGATGCCCGGCTCCAGGCCCTGGTTGTGATGGCTGCCCAGC CCCGCCATGCCGGGGCCTACCACTGCTTTTCAGAGGAGCAGGGGGCGCGGCTGGCTGCTGAAGGCTACCTTGTGG CTGTCGTGGCAGGCCCGTCGGTGACCTTGGAGGCCCGGGCCCCCCTGGAAAACCTGGGGCTGGTGTGGCTGGCGG TGGTGGCCCTGGGGGCTGTGTGCCTGGTGCTGCTGCTGCTGGTGCTGTCATTGCGCCGGCGGCTGCGGGAAGAGC TGGAGAAAGGGGCCAAGGCTACTGAGAGGACCTTGGTGTACCCCCTGGAGCTGCCCAAGGAGCCCACCAGTCCCC CCTTCCGGCCCTGTCCTGAACCAGATGAGAAACTTTGGGATCCTGTCGGTTACTACTATTCAGATGGCTCCCTTA AGATAGTACCTGGGCATGCCCGGTGCCAGCCCGGTGGGGGGCCCCCTTCGCCACCTCCAGGCATCCCAGGCCAGC CTCTGCCTTCTCCAACTCGGCTTCACCTGGGGGGTGGGCGGAACTCAAATGCCAATGGTTACGTGCGCTTACAAC TAGGAGGGGAGGACCGGGGAGGGCTCGGGCACCCCCTGCCTGAGCTCGCGGATGAACTGAGACGCAAACTGCAGC AACGCCAGCCACTGCCCGACTCCAACCCCGAGGAGTCATCAGTATGAGGGGAACCCCCACCGCGTCGGCGGGAAG CGTGGGAG

The MOL5b protein encoded by SEQ ID NO: 16 has 833 amino acid residues and is presented using the one-letter code in Table 5D. The Psort profile for MOL5b predicts that this sequence is likely to be localized at the plasma membrane with a certainty of 0.7000. Table 5D. Encoded MOL5b protein sequence (SEQ ID NO:16)

MAPH AV LLAARLWGLGIGAEV WNLVPRKTVSSGELATWRRFSQTGIQDFLTLTLTEPTGLLYVGARDHA SALGVPVLLLQAVIS EAPVEKKTECIQKGKNNQTECFNFIRFLQPYNASHLYVCGTYAFQPKCTYVNMLTFT LEHGEFEDGKGKCPYDPAKGHAGLLVDGELYSATLNNFLGTEPIILR MGPHHSMKTEYLAFWLNEPHFVGSA YVPESVGSFTGDDDKVYFFFRERAVESDCYAEQWARVARVCKGDMGGARTLQRKWTTFLRARLACSAPNWQL YFNQLQAMHTLQDTS HNTTFFGVFQAQ GDMYLSAICEYQLEEIQRVFEGPYKEYHEEAQKWDRYTDPVPSP RPGSCINNWHRRHGYTSSLELPDNILNFVKKHPLMEEQVGPRWSRPLLVKKGTNFTHLVADRVTGLDGATYTV LFIGTGDGWLLKAVSLGPWvHLIEELQLFDQEPMRSLVLSQSKKLLFAGSRSQLVQLPVADCMKYRSCADCVL ARDPYCA SV TSRCVAVGGHSGSLLIQHVMTSDTSGICNLRGSKKVRPTPK ITvVAGTDLVLPCHLSSNLA HAR TFGGRDLPAEQPGSFLYDARLQALWMAAQPRHAGAYHCFSEEQGARLAAEGYLVAWAGPSVTLEARA PLENLGLVWLAWALGAVCLVLLLLVLSLRRRLREELEKGAKATERTLVYPLELPKEPTSPPFRPCPEPDEKL WDPVGYYYSDGSLKIVPGHARCQPGGGPPSPPPGIPGQPLPSPTRLHLGGGRNSNANGYVRLQLGGEDRGGLG HPLPELADELRRKLQQRQPLPDSNPEESSV

The disclosed nucleic acid sequence for MOL5b has 1695 of 2019 bases (83%) identical to a mouse Semaphorin4C mRNA (GENBANK-ID: S79463) (E= 0.0).

The full MOL5b amino acid sequence has 722 of 834 amino acid residues ( 86%) identical to, and 765 of 834 residues (91%) positive with the amino acid Semaphorin4C HOMOLOG protein from Mouse (S79463_ SEMA_4C_MOUSE) (E= 0.0). The global sequence homology (as defined by FASTA alignment with the full length sequence of this protein) is 91 % amino acid homology and 86 % amino acid identity. Chromosomal Localization MOL5b has been localized to human chromosome 2.

MOL5c

In the present invention, the target sequence identified previously, MOL5b, was subjected to the exon linking process to confirm the sequence. PCR primers were designed by starting at the most upstream sequence available, for the forward primer, and at the most downstream sequence available for the reverse primer. In each case, the sequence was examined, walking inward from the respective termini toward the coding sequence, until a suitable sequence that is either unique or highly selective was encountered, or, in the case ofthe reverse primer, until the stop codon was reached. Such primers were designed based on in silico predictions for the full length cDNA, part (one or more exons) of the DNA or protein sequence ofthe target sequence, or by translated homology ofthe predicted exons to closely related human sequences sequences from other species. These primers were then employed in PCR amplification based on the following pool of human cDNAs: adrenal gland, bone marrow, brain - amygdala, brain - cerebellum, brain - hippocampus, brain - substantia nigra, brain - thalamus, brain -whole, fetal brain, fetal kidney, fetal liver, fetal lung, heart, kidney, lymphoma - Raji, mammary gland, pancreas, pituitary gland, placenta, prostate, salivary gland, skeletal muscle, small intestine, spinal cord, spleen, stomach, testis, thyroid, trachea, uterus. Usually the resulting amplicons were gel purified, cloned and sequenced to high redundancy. The resulting sequences from all clones were assembled with themselves, with other fragments in CuraGen Corporation's database and with public ESTs. Fragments and ESTs were included as components for an assembly when the extent of their identity with another component ofthe assembly was at least 95% over 50 bp. In addition, sequence traces were evaluated manually and edited for corrections if appropriate. These procedures provide the sequence reported below, which is designated MOL5c (Accession Number CG50907-02). This differs from the previously identified sequence, MOL5b, in having 17 different amino acids.

The disclosed novel semaphorin 4C -like nucleic acid of 3112 nucleotides, MOL5c, (also referred to as CG50907-02) is shown in Table 5E. An ORF begins with an ATG initiation codon at nucleotides 104 - 106 and ends with a TGA codon at nucleotides 2603-2605. A putative untranslated region upstream from the initiation codon and downstream from the termination codon is underlined in Table 5E, and the start and stop codons are in bold letters.

Table 5E. MOL5c Nucleotide Sequence (SEQ ID NO:17)

TGCTGCGGGCCCCTCTGGTTTGCTTTCTCTGGCTGTGATTTCTGACCATGTCTTTTCCCTCAGCAGGACAGCTGG CCTGAAGCTCAGAGCCGGGGCGTGCGCCATGGCCCCACACTGGGCTGTCTGGCTGCTGGCAGCAAGGCTGTGGGG CCTGGGCATTGGGGCTGAGGTGTGGTGGAACCTTGTGCCGCGTAAGACAGTGTCTTCTGGGGAGCTGGCCACGGT AGTACGGCGGTTCTCCCAGACCGGCATCCAGGACTTCCTGACACTGACGCTGACGGAGCCCACTGGGCTTCTGTA CGTGGGCGCCAGGGACCATGCCTCTGCACTGGGCGTCCCTGTGTTGCTGCTGCAGGCTGTGATCTCCTGGGAGGC CCCCGTGGAGAAGAAGACTGAGTGTATCCAGAAAGGGAAGAACAACCAGACCGAGTGCTTCAACTTCATCCGCTT CCTGCAGCCCTACAATGCCTCCCACCTGTACGTCTGTGGCACCTACGCCTTCCAGCCCAAGTGCACCTACGTCAA CATGCTCACCTTCACTTTGGAGCATGGAGAGTTTGAAGATGGGAAGGGCAAGTGTCCCTATGACCCAGCTAAGGG CCATGCTGGCCTTCTTGTGGATGGTGAGCTGTACTCGGCCACACTCAACAACTTCCTGGGCACGGAACCCATTAT CCTGCGTAACATGGGGCCCCACCACTCCATGAAGACAGAGTACCTGGCCTTTTGGCTCAACGAACCTCACTTTGT AGGCTCTGCCTATGTACCTGAGAGTGTGGGCAGCTTCACGGGGGACGACGACAAGGTCTACTTCTTCTTCAGGGA GCGGGCAGTGGAGTCCGACTGCTATGCCGAGCAGGTGGTGGCTCGTGTGGCCCGTGTCTGCAAGGGCGATATGGG GGGCGCACGGACCCTGCAGAGGAAGTGGACCACGTTCCTGAAGGCGCGGCTGGCATGCTCTGCCCCGAACTGGCA GCTCTACTTCAACCAGCTGCAGGCGATGCACACCCTGCAGGACACCTCCTGGCACAACACCACCTTCTTTGGGGT TTTTCAAGCACAGTGGGGTGACATGTACCTGTCGGCCATCTGTGAGTACCAGTTGGAAGAGATCCAGCGGGTGTT TGAGGGCCCCTATAAGGAGTACCATGAGGAAGCCCAGAAGTGGGACCGCTACACTGACCCTGTACCCAGCCCTCG GCCTGGCTCGTGCATTAACAACTGGCATCGGCGCCACGGCTACACCAGCTCCCTGGAGCTACCCGACAACATCCT CAACTTCGTCAAGAAGCACCCGCTGATGGAGGAGCAGGTGGGGCCTCGGTGGAGCCGCCCCCTGCTCGTGAAGAA GGGCACCAACTTCACCCACCTGGTGGCCGACCGGGTTACAGGACTTGATGGAGCCACCTATACAGTGCTGTTCAT TGGCACAGGAGACGGCTGGCTGCTCAAGGCTGTGAGCCTGGGGCCCTGGGTTCACCTGATTGAGGAGCTGCAGCT GTTTGACCAGGAGCCCATGAGAAGCCTGGTGCTATCTCAGAGCAAGAAGCTGCTCTTTGCCGGCTCCCGCTCTCA GCTGGTGCAGCTGCCCGTGGCCGACTGCATGAAGTATCGCTCCTGTGCAGACTGTGTCCTCGCCCGGGACCCCTA TTGCGCCTGGAGCGTCAACACCAGCCGCTGTGTGGCCGTGGGTGGCCACTCTGGATCTCTACTGATCCAGCATGT GATGACCTCGGACACTTCAGGCATCTGCAACCTCCGTGGCAGTAAGAAAGTCAGGCCCACTCCCAAAAACATCAC GGTGGTGGCGGGCACAGACCTGGTGCTGCCCTGCCACCTCTCCTCCAACTTGGCCCATGCCCGCTGGACCTTTGG GGGCCGGGACCTGCCTGCGGAACAGCCCGGGTCCTTCCTCTACGATGCCCGGCTCCAGGCCCTGGTTGTGATGGC TGCCCAGCCCCGCCATGCCGGGGCCTACCACTGCTTTTCAGAGGAGCAGGGGGCGCGGCTGGCTGCTGAAGGCTA CCTTGTGGCTGTCGTGGCAGGCCCGTCGGTGACCTTGGAGGCCCGGGCCCCCCTGGAAAACCTGGGGCTGGTGTG GCTGGCGGTGGTGGCCCTGGGGGCTGTGTGCCTGGTGCTGCTGCTGCTGGTGCTGTCATTGCGCCGGCGGCTGCG GGAAGAGCTGGAGAAAGGGGCCAAGGCTACTGAGAGGACCTTGGTGTACCCCCTGGAGCTGCCCAAGGAGCCCAC CAGTCCCCCCTTCCGGCCCTGTCCTGAACCAGATGAGAAACTTTGGGATCCTGTCGGTTACTACTATTCAGATGG CTCCCTTAAGATAGTACCTGGGCATGCCCGGTGCCAGCCCGGTGGGGGGCCCCCTTCGCCACCTCCAGGCATCCC AGGCCAGCCTCTGCCTTCTCCAACTCGGCTTCACCTGGGGGGTGGGCGGAACTCAAATGCCAATGGTTACGTGCG CTTACAACTAGGAGGGGAGGACCGGGGAGGGCTCGGGCACCCCCTGCCTGAGCTCGCGGATGAACTGAGACGCAA ACTGCAGCAACGCCAGCCACTGCCCGACTCCAACCCCGAGGAGTCATCAGTATGAGGGGAACCCCCACCGCGTCG GCGGGAAGCGTGGGAGGTGTAGCTCCTACTTTTGCACAGGCACCAGCTACCTCAGGGACATGGCACGGGCACCTG CTCTGTCTGGGACAGATACTGCCCAGCACCCACCCGGCCATGAGGACCTGCTCTGCTCAGCACGGGCACTGCCAC TTGGTGTGGCTCACCAGGGCACCAGCCTCGCAGAAGGCATCTTCCTCCTCTCTGTGAATCACAGACACGCGGGAC CCCAGCCGCCAAAACTTTTCAAGGCAGAAGTTTCAAGATGTGTGTTTGTCTGTATTTGCACATGTGTTTGTGTGT GTGTGTATGTGTGTGTGCACGCGCGTGCGCGCTTGTGGCATAGCCTTCCTGTTTCTGTCAAGTCTTCCCTTGGCC TGGGTCCTCCTGGTGAGTCATTGGAGCTATGAAGGGGAAGGGGTCGTATCACTTTGTCTCTCCTACCCCCACTGC CCCGAGTGTCGGGCAGCGATGTACATATGGAGGTGGG

The MOL5c protein encoded by SEQ ID NO: 17 has 833 amino acid residues and is presented using the one-letter code in Table 5F. The Psort profile for MOL5c predicts that this sequence has a signal peptide and the signal peptide is predicted by SignalP to be cleaved between amino acid 20 and 21 : GIG-AE. This sequence is likely to be localized at the mitochondrial inner membrane with a certainty of 0.8000 and the plasma membrane with a certainty of 0.7000.

Table 5F. Encoded MOL5c protein sequence (SEQ ID NO: 18)

MAPH AVWLLAARLWGLGIGAEVW NLVPRKTVSSGELATVVRRFSQTGIQDFLTLTLTEPTGLLYVGARDHA SALGVPVLLLQAVIS EAPVEKKTECIQKGKMNQTECFNFIRFLQPYNASHLYVCGTYAFQP CTYV LTFT LEHGEFEDGKGKCPYDPAKGHAGLLVDGELYSATLNWFLGTEPIILRNMGPHHSMKTEYLAF LNEPHFVGSA YVPESVGSFTGDDDKVYFFFRERAVESDCYAEQWARVARVCKGDMGGARTLQRK TTFLKARLACSAPNWQL YFNQLQAMHTLQDTS HNTTFFGVFQAQ GDMYLSAICEYQLEEIQRVFEGPYKEYHEEAQK DRYTDPVPSP RPGSCIN WHRRHGYTSSLELPDNILNFVKKHPLMEEQVGPRWSRPLLVKKGTNFTHLVADRVTGLDGATYTV LFIGTGDG LL AVSLGPWVHLIEELQLFDQEPMRSLVLSQSK LLFAGSRSQLVQLPVADCMKYRSCADCVL ARDPYCAWSVNTSRCVAVGGHSGSLLIQHVMTSDTSGICNLRGSKKVRPTPKNITWAGTDLVLPCHLSSNLA HARWTFGGRDLPAEQPGSFLYDARLQALWMAAQPRHAGAYHCFSEEQGARLAAEGYLVAWAGPSVTLEARA PLENLGLV LAVVALGAVCLVLLLLVLSLRRRLREELEKGAKATERTLVYPLELPKEPTSPPFRPCPEPDEKL WDPVGYYYSDGSLKIVPGHARCQPGGGPPSPPPGIPGQPLPSPTRLHLGGGRNSNANGYVRLQLGGEDRGGLG HPLPELADELRRKLQQRQPLPDSNPEESSV

The disclosed nucleic acid sequence for MOL5c has 2879 of 2906 bases (99%) identical to a gb:GENBANK-ID:AB051526|acc:AB051526.1 mRNA from Homo sapiens (Homo sapiens mRNA for KIAA1739 protein, partial eds) (E= 0.0).

The full MOL5 amino acid sequence has 722 of 834 amino acid residues (86%) identical to, and 765 of 834 amino acid residues (91%) similar to, the 834 amino acid residue ptnr:SWISSPROT-ACC:Q64151 protein from Mus musculus (Mouse)

(SEMAPHORIN 4C PRECURSOR (SEMAPHORIN I) (SEMA I) (SEMAPHORIN C- LIKE 1 ) (M-SEMA F)) (E= 0.0). The global sequence homology (as defined by FASTA alignment with the full length sequence of this protein) is 91%> amino acid homology and 86% amino acid identity. The presence of identifiable domains in the protein disclosed herein was determined by searches versus domain databases such as Pfam, PROSITE, ProDom, Blocks or Prints and then identified by the Interpro domain accession number. Significant domains are summarized in Table 5G.

Table 5G: Domain similarities for MOL5c

Scores for sequence family classi ication (score includes all domains) :

Model Description Score E-value N

Sema Sema domain 664.4 5.8e-196 1

Plexin_repeat Plexin repeat 25.8 0.001 1 ig Immunoglobulin domain 8.5 0.44 1 integrin_B Integrins , beta chain 7.0 0.04 1

Parsed for domains :

Model Domain seq-f seq-t hmm-f hmm-t score E -value

Sema l/l 53 481 .. 1 490 [] 664.4 5.8e-196 integrin_B 1/1 505 519 .. 1 14 [. 7.0 0.04

Plexin_repeat l/l 499 551 .. 1 67 [] 25.8 0.001 ig 1/1 570 6₂9 .. 1 45 [] 8.5 0.44

The Sema domain occurs in semaphorins, which are a large family of secreted and transmembrane proteins, some of which function as repellent signals during axon guidance. Sema domains also occur in a hepatocyte growth factor receptor, in SEX protein (Goodman et al., 1998, Cell 95: 903-916) and in viral proteins.

The presence of these domains indicates that MOL5c likely has properties similar to those of other proteins known to contain this/these domain(s) and similar to the properties of these domains.

Chromosomal Localization

MOL5c maps to chromosome 2. This assignment was made using mapping information associated with genomic clones, public genes and ESTs sharing sequence identity with the disclosed sequence and CuraGen Corporation's Electronic Northern bioinformatic tool.

Tissue Expression

MOL5c is expressed in at least the following tissues: adrenal gland, bone marrow, brain - amygdala, brain - cerebellum, brain - hippocampus, brain - substantia nigra, brain - thalamus, brain -whole, fetal brain, fetal kidney, fetal liver, fetal lung, heart, kidney, lymphoma - Raji, mammary gland, pancreas, pituitary gland, placenta, prostate, salivary gland, skeletal muscle, small intestine, spinal cord, spleen, stomach, testis, thyroid, trachea and uterus. Expression information was derived from the tissue sources ofthe sequences that were included in the derivation ofthe sequence of MOL5c. MOL5d

The disclosed novel semaphorin 4C -like nucleic acid of 1914 nucleotides, MOL5d, (also referred to as CG50907-03) is shown in Table 5H. An ORF begins with an ATG initiation codon at nucleotides 104 - 106 and ends with a TGA codon at nucleotides 2603-2605. A putative untranslated region upstream from the initiation codon and downstream from the termination codon is underlined in Table 5H, and the start and stop codons are in bold letters.

Table 5H. MOL5d Nucleotide Sequence (SEQ ID NO: 119)

CTCGAGCTCCAAGGTCACCGACGGGCCTGCCACGACAGCCACAAGGTAGCCTTCAGCAGCCAGCCGCGCCCCCTG CTCCTCTGAAAAGCAGTGGTAGGCCCCGGCATGGCGGGGCTGGGCAGCCATCACAACCAGGGCCTGGAGCCGGGC ATCGTAGAGGAAGGACCCGGGCTGTTCCGCAGGCAGGTCCCGGCCCCCAAAGGTCCAGCGGGCATGGGCCAAGTT GGAGGAGAGGTGGCAGGGCAGCACCAGGTCTGTGCCCGCCACCACCGTGATGTTTTTGGGAGTGGGCCTGACTTT CTTACTGCCACGGAGGTTGCAGATGCCTGAAGTGTCCGAGGTCATCACATGCTGGATCAGTAGAGATCCAGAGTG GCCACCCACGGCCACACAGCGGCTGGTGTTGACGCTCCAGGCGCAATAGGGGTCCCGGGCGAGGACACAGTCTGC ACAGGAGCGATACTTCATGCAGTCGGCCACGGGCAGCTGCACCAGCTGAGAGCGGGAGCCGGCAAAGAGCAGCTT CTTGCTCTGAGATAGCACCAGGCTTCTCATGGGCTCCTGGTCAAACAGCTGCAGCTCCTCAATCAGGTGAACCCA GGGCCCCAGGCTCACAGCCTTGAGCAGCCAGCCGTCTCCTGTGCCAATGAACAGCACTGTATAGGTGGCTCCATC AAGTCCTGTAACCCGGTCGGCCACCAGGTGGGTGAAGTTGGTGCCCTTCTTCACGAGCAGGGGGCGGCTCCACCG AGGCCCCACCTGCTCCTCCATCAGCGGGTGCTTCTTGACGAAGTTGAGGATGTTGTCGGGTAGCTCCAGGGAGCT GGTGTAGCCGTGGCGCCGATGCCAGTTGTTAATGCACGAGCCAGGCCGAGGGCTGGGTACAGGGTCAGTGTAGCG GTCCCACTTCTGGGCTTCCTCATGGTACTCCTTATAGGGGCCCTCAAACACCCGCTGGATCTCTTCCAACTGGTA CTCACAGATGGCCGACAGGTACATGTCACCCCACTGTGCTTGAAAAACCCCAAAGAAGGTGGTGTTGTGCCAGGA GGTGTCCTGCAGGGTGTGCATCGCCTGCAGCTGGTTGAAGTAGAGCTGCCAGTTCGGGGCAGAGCATGCCAGCCG CGCCTTCAGGAACGTGGTCCACTTCCTCTGCAGGGTCCGTGCGCCCCCCATATCGCCCTTGCAGACACGGGCCAC ACGAGCCACCACCTGCTCGGCATAGCAGTCGGACTCCACTGCCCGCTCCCTGAAGAAGAAGTAGACCTTGTCGTC GTCCCCCGTGAAGCTGCCCACACTCTCAGGTACATAGGCAGAGCCTACAAAGTGAGGTTCGTTGAGCCAAAAGGC CAGGTACTCTGTCTTCATGGAGTGGTGGGGCCCCATGTTACGCAGGATAATGGGTTCCGTGCCCAGGAAGTTGTT GAGTGTGGCCGAGTACAGCTCACCATCCACAAGAAGGCCAGCATGGCCCTTAGCTGGGTCATAGGGACACTTGCC CTTCCCATCTTCAAACTCTCCATGCTCCAAAGTGAAGGTGAGCATGTTGACGTAGGTGCACTTGGGCTGGAAGGC GTAGGTGCCACAGACGTACAGGTGGGAGGCATTGTAGGGCTGCAGGAAGCGGATGAAGTTGAAGCACTCGGTCTG GTTGTTCTTCCCTTTCTGGATACACTCAGTCTTCTCCTCCACGGGGGCCTCCCAGGAGATCGCTCCTTGCAGCTC CAGGGCCTCCATGCTGAAGGCAAACAGGGCCTCTCGGGCGCCCACGTACAGAAGCCCAGTGGGCTCCGTCAGCGT CAGTGTCAGGAAGTCCTGGATGCCGGTCTGGGAGAACCGCCGTACTACCGTGGCCAGCTCCCCAGAAGACACTGT CTTACGCGGCACAAGGTTCCACCACACCTCAGCAGATCT

The nucleic acid sequence for MOL5d is 99% identical to the 2156 sequence disclosed in WO200078802-A2 with a priority date of June 23, 1999.

The MOL5d protein encoded by SEQ ID NO: 120 has 634 amino acid residues and is presented using the one-letter code in Table 51. The Psort profile for MOL5d predicts that this sequence has a signal peptide and the signal peptide is predicted by SignalP to be cleaved between amino acid 20 and 21 : GIG-AE. This sequence is likely to be a type 1 membrane protein (ECD proposed for immunization) localized at the mitochondrial inner membrane with a certainty of 0.8000 and the plasma membrane with a certainty of 0.7000. Table 51. Encoded MOL5d protein sequence (SEQ ID NO: 120)

AEVWWNLVPRKTVSSGELATWRRFSQTGIQDFLTLTLTEPTGLLYVGAREALFAFSMEALELQGAIS EAPV EEKTECIQKGKNNQTECFNFIRFLQPYNASHLYVCGTYAFQPKCTYVMMLTFTLEHGEFEDGKGKCPYDPAKG HAGLLVDGELYSATLNNFLGTEPIILRNMGPHHSMKTEYLAF LNEPHFVGSAYVPESVGSFTGDDDKVYFFF RERAVESDCYAEQWARVARVCKGDMGGARTLQRKWTTFLKARLACSAPNWQLYFNQLQAMHTLQDTSWHNTT FFGVFQAQWGDMYLSAICEYQLEEIQRVFEGPYKEYHEEAQKWDRYTDPVPSPRPGSCI WHRRHGYTSSLE LPDNILNFVKKHPLMEEQVGPR SRPLLVKKGTNFTHLVADRVTGLDGATYTVLFIGTGDGWLLKAVSLGP V HLIEELQLFDQEPMRSLVLSQSKKLLFAGSRSQLVQLPVADCMKYRSCADCVLARDPYCAWSvNTSRCvAVGG HSGSLLIQHVMTSDTSGICNLRGSKKVRPTPKNITWAGTDLVLPCHLSSNLAHAR TFGGRDLPAEQPGSFL YDARLQALWMAAQPRHAGAYHCFΞEEQGARLAAEGYLVAWAGPSVTLE

The disclosed amino acid sequence for MOL5d is 99% identical to Q9C0C4, June 2001, KIAA 1739 PROTEIN - Homo sapiens (Human), 963 aa (fragment). The amino acid sequence for MOL5d is also 99% identical to the 624 aa sequence with Accession number: AAB48378 disclosed in WO200078802-A2 with a priority date of June 23, 1999. The amino acid sequence for MOL5d is also 98.9% identical to the 833aa sequence with Accession number: AAE03640 disclosed in WO200142285-A2 with a priority date of December 10, 1999.

MOL5d has been found to contain the following domains from the Pfam library: Sema domain, Plexin repeat, Immunoglobulin domain, Integrins, and beta chain domains. Potential Role(s) of MOL5d in Tumorgenesis: Semaphorin are involved in neuronal axonal migration. Recently they have been associated with migration, invasion and apoptosis of tumor cells and endothelial cells. MOL5d (Semaphorin 4C-like protein) is overexpressed in the metastatic variant SW620 compared with SW480. It is also generally more expressed in cell lines derived from metastasis like the melanomas SK-Mel5 and HS688b and the liver met of gastric NCIN87. In the panel of tumor tissues, it is strongly induced in lung tumors and show overall overexpression in all other tumors. It potential role in tumorogenesis is likely to be to stimulate migration of tumor cells and therefore increase their ability to metastatize. Impact of therapeutic targeting of MOL5d : Targeting with a human monoclonal antibody of MOL5d that results in an inhibition ofthe activity of this protein, preferably as it relates to its stimulation of migration and/or apoptotic/survival activity in tumor cells, specifically lung tumor cells, will have therapeutic effect on all solid tumor that depend on its activity, preferably on lung tumors. MOL5e

The disclosed novel semaphorin 4C -like nucleic acid of 1914 nucleotides, MOL5e, (also referred to as 170645595) is shown in Table 5J. An ORF begins with an AGA initiation codon at nucleotides 1-3 and ends with a GAG codon at nucleotides 1912- 1914. The start and stop codons are in bold letters. Because the start and stop codons are not traditional initiation or termination codons, MOL5e could be a partial reading frame extending further in the 5' and/or 3' directions.

Table 5J. MOL5e Nucleotide Sequence (SEQ ID NO:121)

AGATCTGCTGAGGTGTGGTGGAACCTTGTGCCGCGTAAGACAGTGTCTTCTGGGGAGCTGGCCACGGTAGTACGG CGGTTCTCCCAGACCGGCATCCAGGACTTCCTGACACTGACGCTGACGGAGCCCACTGGGCTTCTGTACGTGGGC GCCCGAGAGGCCCTGTTTGCCTTCAGCATGGAGGCCCTGGAGCTGCAAGGAGCGATCTCCTGGGAGGCCCCCGTG GAGGAGAAGACTGAGTGTATCCAGAAAGGGAAGAACAACCAGACCGAGTGCTTCAACTTCATCCGCTTCCTGCAG CCCTACAATGCCTCCCACCTGTACGTCTGTGGCACCTACGCCTTCCAGCCCAAGTGCACCTACGTCAACATGCTC ACCTTCACTTTGGAGCATGGAGAGTTTGAAGATGGGAAGGGCAAGTGTCCCTATGACCCAGCTAAGGGCCATGCT GGCCTTCTTGTGGATGGTGAGCTGTACTCGGCCACACTCAACAACTTCCTGGGCACGGAACCCATTATCCTGCGT AACATGGGGCCCCACCACTCCATGAAGACAGAGTACCTGGCCTTTTGGCTCAACGAACCTCACTTTGTAGGCTCT GCCTATGTACCTGAGAGTGTGGGCAGCTTCACGGGGGACGACGACAAGGTCTACTTCTTCTTCAGGGAGCGGGCA GTGGAGTCCGACTGCTATGCCGAGCAGGTGGTGGCTCGTGTGGCCCGTGTCTGCAAGGGCGATATGGGGGGCGCA CGGACCCTGCAGAGGAAGTGGACCACGTTCCTGAAGGCGCGGCTGGCATGCTCTGCCCCGAACTGGCAGCTCTAC TTCAACCAGCTGCAGGCGATGCACACCCTGCAGGACACCTCCTGGCACAACACCACCTTCTTTGGGGTTTTTCAA GCACAGTGGGGTGACATGTACCTGTCGGCCATCTGTGAGTACCAGTTGGAAGAGATCCAGCGGGTGTTTGAGGGC CCCTATAAGGAGTACCATGAGGAAGCCCAGAAGTGGGACCGCTACACTGACCCTGTACCCAGCCCTCGGCCTGGC TCGTGCATTAACAACTGGCATCGGCGCCACGGCTACACCAGCTCCCTGGAGCTACCCGACAACATCCTCAACTTC GTCAAGAAGCACCCGCTGATGGAGGAGCAGGTGGGGCCTCGGTGGAGCCGCCCCCTGCTCGTGAAGAAGGGCACC AACTTCACCCACCTGGTGGCCGACCGGGTTACAGGACTTGATGGAGCCACCTATACAGTGCTGTTCATTGGCACA GGAGACGGCTGGCTGCTCAAGGCTGTGAGCCTGGGGCCCTGGGTTCACCTGATTGAGGAGCTGCAGCTGTTTGAC CAGGAGCCCATGAGAAGCCTGGTGCTATCTCAGAGCAAGAAGCTGCTCTTTGCCGGCTCCCGCTCTCAGCTGGTG CAGCTGCCCGTGGCCGACTGCATGAAGTATCGCTCCTGTGCAGACTGTGTCCTCGCCCGGGACCCCTATTGCGCC TGGAGCGTCAACACCAGCCGCTGTGTGGCCGTGGGTGGCCACTCTGGATCTCTACTGATCCAGCATGTGATGACC TCGGACACTTCAGGCATCTGCAACCTCCGTGGCAGTAAGAAAGTCAGGCCCACTCCCAAAAACATCACGGTGGTG GCGGGCACAGACCTGGTGCTGCCCTGCCACCTCTCCTCCAACTTGGCCCATGCCCGCTGGACCTTTGGGGGCCGG GACCTGCCTGCGGAACAGCCCGGGTCCTTCCTCTACGATGCCCGGCTCCAGGCCCTGGTTGTGATGGCTGCCCAG CCCCGCCATGCCGGGGCCTACCACTGCTTTTCAGAGGAGCAGGGGGCGCGGCTGGCTGCTGAAGGCTACCTTGTG GCTGTCGTGGCAGGCCCGTCGGTGACCTTGGAGCTCGAG

The reverse complement of MOL5e is shown in Table 5K.

Table 5K. MOL5e Reverse Complement Nucleotide Sequence (SEQ ID

NO:122)

CTCGAGCTCCAAGGTCACCGACGGGCCTGCCACGACAGCCACAAGGTAGCCTTCAGCAGCCAGCCGCGCCCCCTG CTCCTCTGAAAAGCAGTGGTAGGCCCCGGCATGGCGGGGCTGGGCAGCCATCACAACCAGGGCCTGGAGCCGGGC ATCGTAGAGGAAGGACCCGGGCTGTTCCGCAGGCAGGTCCCGGCCCCCAAAGGTCCAGCGGGCATGGGCCAAGTT GGAGGAGAGGTGGCAGGGCAGCACCAGGTCTGTGCCCGCCACCACCGTGATGTTTTTGGGAGTGGGCCTGACTTT CTTACTGCCACGGAGGTTGCAGATGCCTGAAGTGTCCGAGGTCATCACATGCTGGATCAGTAGAGATCCAGAGTG GCCACCCACGGCCACACAGCGGCTGGTGTTGACGCTCCAGGCGCAATAGGGGTCCCGGGCGAGGACACAGTCTGC ACAGGAGCGATACTTCATGCAGTCGGCCACGGGCAGCTGCACCAGCTGAGAGCGGGAGCCGGCAAAGAGCAGCTT CTTGCTCTGAGATAGCACCAGGCTTCTCATGGGCTCCTGGTCAAACAGCTGCAGCTCCTCAATCAGGTGAACCCA GGGCCCCAGGCTCACAGCCTTGAGCAGCCAGCCGTCTCCTGTGCCAATGAACAGCACTGTATAGGTGGCTCCATC AAGTCCTGTAACCCGGTCGGCCACCAGGTGGGTGAAGTTGGTGCCCTTCTTCACGAGCAGGGGGCGGCTCCACCG AGGCCCCACCTGCTCCTCCATCAGCGGGTGCTTCTTGACGAAGTTGAGGATGTTGTCGGGTAGCTCCAGGGAGCT GGTGTAGCCGTGGCGCCGATGCCAGTTGTTAATGCACGAGCCAGGCCGAGGGCTGGGTACAGGGTCAGTGTAGCG GTCCCACTTCTGGGCTTCCTCATGGTACTCCTTATAGGGGCCCTCAAACACCCGCTGGATCTCTTCCAACTGGTA CTCACAGATGGCCGACAGGTACATGTCACCCCACTGTGCTTGAAAAACCCCAAAGAAGGTGGTGTTGTGCCAGGA GGTGTCCTGCAGGGTGTGCATCGCCTGCAGCTGGTTGAAGTAGAGCTGCCAGTTCGGGGCAGAGCATGCCAGCCG CGCCTTCAGGAACGTGGTCCACTTCCTCTGCAGGGTCCGTGCGCCCCCCATATCGCCCTTGCAGACACGGGCCAC ACGAGCCACCACCTGCTCGGCATAGCAGTCGGACTCCACTGCCCGCTCCCTGAAGAAGAAGTAGACCTTGTCGTC GTCCCCCGTGAAGCTGCCCACACTCTCAGGTACATAGGCAGAGCCTACAAAGTGAGGTTCGTTGAGCCAAAAGGC CAGGTACTCTGTCTTCATGGAGTGGTGGGGCCCCATGTTACGCAGGATAATGGGTTCCGTGCCCAGGAAGTTGTT GAGTGTGGCCGAGTACAGCTCACCATCCACAAGAAGGCCAGCATGGCCCTTAGCTGGGTCATAGGGACACTTGCC CTTCCCATCTTCAAACTCTCCATGCTCCAAAGTGAAGGTGAGCATGTTGACGTAGGTGCACTTGGGCTGGAAGGC GTAGGTGCCACAGACGTACAGGTGGGAGGCATTGTAGGGCTGCAGGAAGCGGATGAAGTTGAAGCACTCGGTCTG GTTGTTCTTCCCTTTCTGGATACACTCAGTCTTCTCCTCCACGGGGGCCTCCCAGGAGATCGCTCCTTGCAGCTC CAGGGCCTCCATGCTGAAGGCAAACAGGGCCTCTCGGGCGCCCACGTACAGAAGCCCAGTGGGCTCCGTCAGCGT CAGTGTCAGGAAGTCCTGGATGCCGGTCTGGGAGAACCGCCGTACTACCGTGGCCAGCTCCCCAGAAGACACTGT CTTACGCGGCACAAGGTTCCACCACACCTCAGCAGATCT

The MOL5e protein encoded by SEQ ID NO: 123 has 638 amino acid residues and is presented using the one-letter code in Table 5L.

Table 5L. Encoded MOL5e protein sequence (SEQ ID NO: 123)

RSAEVW NLVPR TVSSGELATWRRFSQTGIQDFLTLTLTEPTGLLYVGAREALFAFSMEALELQGAIS EA PVEEKTECIQKGKNNQTECFNFIRFLQPY ASHLYVCGTYAFQPKCTYVNMLTFTLEHGEFEDGKGKCPYDPA KGHAGLLVDGELYSATLMNFLGTEPIILRNMGPHHSM TEYLAF LNEPHFVGSAYVPESVGSFTGDDDKVYF FFRERAVESDCYAEQWARVARVC GDMGGARTLQR WTTFL ARLACSAPNWQLYFNQLQAMHTLQDTSWH TTFFGVFQAQWGDMYLSAICEYQLEEIQRVFEGPYKEYHEEAQKWDRYTDPVPSPRPGSCINNWHRRHGYTSS LELPDNILNFVRKHPLMEEQvGPRWSRPLLVKKGTNFTHLvADRVTGLDGATYTVLFIGTGDGWLLKAVSLGP VHL1EELQLFDQEPMRSLVLSQSKKLLFAGSRSQLVQLPVADCMKYRSCADCVLARDPYCAWSVNTSRCVAV GGHSGSLLIQHVMTSDTSGICNLRGSKKVRPTPKNITVVAGTDLVLPCHLSSNLAHARWTFGGRDLPAEQPGS FLYDARLQALWMAAOPRHAGAYHCFSEEQGARLAAEGYLVAWAGPSVTLELE

MOL5f

The disclosed novel semaphorin 4C -like nucleic acid of 1914 nucleotides, MOL5f, (also referred to as 170645599) is shown in Table 5M. An ORF begins with an AGA initiation codon at nucleotides 1-3 and ends with a GAG codon at nucleotides 1912-1914. The start and stop codons are in bold letters. Because the start and stop codons are not traditional initiation or termination codons, MOL5f could be a partial reading frame extending further in the 5' and/or 3' directions.

Table 5M. MOL5f Nucleotide Sequence (SEQ ID NO:124)

AGATCTGCTGAGGTGTGGTGGAACCTTGTGCCGCGTAAGACAGTGTCTTCTGGGGAGCTGGCCACGGTAGTACGG CGGTTCTCCCAGACCGGCATCCAGGACTTCCTGACACTGACGCTGACGGAGCCCACTGGGCTTCTGTACGTGGGC GCCCGAGAGGCCCTGTTTGCCTTCAGCATGGAGGCCCTGGAGCTGCAAGGAGCGATCTCCTGGGAGGCCCCCGTG GAGAAGAAGACTGAGTGTATCCAGAAAGGGAAGAACAGCCAGACCGAGTGCTTCAACTTCATCCGCTTCCTGCAG CCCTACAATGCCTCCCACCTGTACGTCTGTGGCACCTACGCCTTCCAGCCCAAGTGCACCTACGTCAACATGCTC ACCTTCACTTTGGAGCATGGAGAGTTTGAAGATGGGAAGGGCAAGTGTCCCTATGACCCAGCTAAGGGCCATGCT GGCCTTCTTGTGGATGGTGAGCTGTACTCGGCCACACTCAACAACTTCCTGGGCACGGAACCCATTATCCTGCGT AACATGGGGCCCCACCACTCCATGAAGACAGAGTACCTGGCCTTTTGGCTCAACGAACCTCACTTTGTAGGCTCT GCCTATGTACCTGAGAGTGTGGGCAGCTTCACGGGGGACGACGACAAGGTCTACTTCTTCTTCAGGGAGCGGGCA GTGGAGTCCGACTGCTATGCCGAGCAGGTGGTGGCTCGTGTGGCCCGTGTCTGCAAGGGCGATATGGGGGGCGCA CGGACCCTGCAGAGGAAGTGGACCACGTTCCTGAAGGCGCGGCTGGCATGCTCTGCCCCGAACTGGCAGCTCTAC TTCAACCAGCTGCAGGCGATGCACACCCTGCAGGACACCTCCTGGCACAACACCACCTTCTTTGGGGTTTTTCAA GCACAGTGGGGTGACATGTACCTGTCGGCCATCTGTGAGTACCAGTTGGAAGAGATCCAGCGGGTGTTTGAGGGC CCCTATAAGGAGTACCATGAGGAAGCCCAGAAGTGGGACCGCTACACTGACCCTGTACCCAGCCCTCGGCCTGGC TCGTGCATTAACAACTGGCATCGGCGCCACGGCTACACCAGCTCCCTGGAGCTACCCGACAACATCCTCAACTTC GTCAAGAAGCACCCGCTGATGGAGGAGCAGGTGGGGCCTCGGTGGAGCCGCCCCCTGCTCGTGAAGAAGGGCACC AACTTCACCCACCTGGTGGCCGACCGGGTTACAGGACTTGATGGAGCCACCTATACAGTGCTGTTCATTGGCACA GGAGACGGCTGGCTGCTCAAGGCTGTGAGCCTGGGGCCCTGGGTTCACCTGATTGAGGAGCTGCAGCTGTTTGAC CAGGAGCCCATGAGAAGCCTGGTGCTATCTCAGAGCAAGAAGCTGCTCTTTGCCGGCTCCCGCTCTCAGCTGGTG CAGCTGCCCGTGGCCGACTGCATGAAGTATCGCTCCTGTGCAGACTGTGTCCTCGCCCGGGACCCCTATTGCGCC TGGAGCGTCAACACCAGCCGCTGTGTGGCCGTGGGTGGCCACTCTGGATCTCTACTGATCCAGCATGTGATGACC TCGGACACTTCAGGCATCTGCAACCTCCGTGGCAGTAAGAAAGTCAGGCCCACTCCCAAAAACATCACGGTGGTG GCGGGCACAGACCTGGTGCTGCCCTGCCACCTCTCCTCCAACTTGGCCCATGCCCGCTGGACCTTTGGGGGCCGG GACCTGCCTGCGGAACAGCCCGGGTCCTTCCTCTACGATGCCCGGCTCCAGGCCCTGGTTGTGATGGCTGCCCAG CCCCGCCATGCCGGGGCCTACCACTGCTTTTCAGAGGAGCAGGGGGCGCGGCTGGCTGCTGAAGGCTACCTTGTG GCTGTCGTGGCAGGCCCGTCGGTGACCTTGGAGCTCGAG

The MOL5f protein encoded by SEQ ID NO: 125 has 638 amino acid residues and is presented using the one-letter code in Table 5N.

Table 5N. Encoded MOL5f protein sequence (SEQ ID NO: 125)

RSAEVWWNLVPRKTVSSGELATWRRFSQTGIQDFLTLTLTEPTGLLYVGAREALFAFSMEALELQGAISWEA PVEKKTECIQKGKNSQTECFNFIRFLQPYNASHLYVCGTYAFQPKCTYVNMLTFTLEHGEFEDGKGKCPYDPA KGHAGLLVDGELYSATLN FLGTEPIILR MGPHHSMKTEYLAF LNEPHFVGSAYVPESVGSFTGDDDKVYF FFRERAVESDCYAEQWARVARVCKGDMGGARTLQRK TTFLKARLACSAPN QLYFNQLQAMHTLQDTS H TTFFGVFQAQWGDMYLSAICEYQLEEIQRVFEGPYKEYHEEAQKWDRYTDPVPSPRPGSCI N HRRHGYTSS LELPDNILNFVKKHPLMEEQVGPRWSRPLLVKKGTNFTHLVADRVTGLDGATYTVLFIGTGDGWLLKAVSLGP WVHLIEELQLFDQEPMRSLVLSQSKKLLFAGSRSQLVQLPVADCMKYRSCADCVLARDPYCA SVNTSRCVAV GGHSGSLLIQHVMTSDTSGICNLRGSKKVRPTPKNITWAGTDLVLPCHLSSNLAHAR TFGGRDLPAEQPGS FLYDARLQALWMAAQPRHAGAYHCFSEEQGARLAAEGYLVAWAGPSVTLELE

Table 5O shows a ClustalW alignment ofthe MOL5 variants.

Table 5O. ClustalW alignment of MOL5 variants

10 20 30 40 50 60

MOL5a MAPHWAVWLLAARLWGLGIG 60 MOL5b MAPH AVWLLAARL GLGIGg /WWNLVPRKTVSSGELATWRRFSQTGIQDFLTLTLT. 60 MOL5c MAPHWAV LLAARL GLGIGB T W LVPR TVSSGELATWRRFSQTGIQDFLTLTLT: 60 MOL5d TWWNLVPRKTVSSGELAT RRFSQTGIQDFLTLTLT: 40 OL5e -RS / WNLVPRKTVSSGELATWRRFSQTGIQDFLTLTLTJ 42 OL5f -RSg WWNLVPRKTVSSGELATWRRFSQTGIQDFLTLTLTE 42

130 140 150 160 170 180 OL5 33iι.»'tf«mnwfl mw*> >m ιt*!^χi πsn MOL5b ώHLYVCGTYAFQPKCTYVNMLTFTLEHGEFEDGKGKCPYDPAKGHAGLLVDGELYSA MOL5C iSHLYvCGTYAFQPKCTYVNMLTFTLEHGEFEDGKGKCPYDPAKGHAGLLVDGELYSA MOL5d iSHLYVCGTYAFQPKCTYVNMLTFTLEHGEFEDG GKCPYDPAKGHAGLLVDGELYSA MOL5e ώHLYVCGTYAFQPKCTYVNMLTFTLEHGEFEDGKGKCPYDPAKGHAGLLVDGELYSA¹ MOL5f SHLYVCGTYAFQPKCTYVNMLTFTLEHGEFEDGKGKCPYDPAKGHAGLLVDGELYSA'

190 200 210 220 230 240

MOL5a -OTFLGTEPIILR MGPHHSMKTEYLAF L EPHFVGSAYVPESVGSFTGDDDKVYFI3F OL5b .OTSTFLGTEPIILR MGPHHSMKTEYLAF LNEPHFVGSAYVPESVGSFTGDDDi VYFFF MOLSc .NNFLGTEPIILRNMGPHHSMKTEYLAF L EPHFVGSAYVPESVGSFTGDDD VYFFFi MOL5d .N FLGTEPIILRNMGPHHSMKTEYLAF LNEPHFVGSAYVPESVGSFTGDDDKVYFFF' MOL5e N FLGTEPIILRNMGPHHSMKTEYLAF LNEPHFVGSAYVPESVGSFTGDDDKVYFFFJ MOL5f NFLGTEPIILRNMGPHHSMKTEYLAF LNEPHFVGSAYVPESVGSFTGDDDKVYFFFR

250 260 270 280 290 300

ERAVESDCYAEQWARVARVCKGDMGGARTLQRKWTTFLKARLACSAPN QLYF QLQAM ERAVESDCYAEQWARVARVCKGDMGGARTLQRK TTFL ARLACSAPNWQLYFNQLQAM

ERAVESDCYAEQWARVARVCKGDMGGARTLQRKWTTFLKARLACSAPNWQLYFNQLQAMI.SE

ERAVESDGYAEQWARVARVCKGDMGGARTLQRKWTTFLKARLACSAPNWQLYFNQLQAM

ERAVESDCYAEQWARVARVCKGDMGGARTLQRKWTTFLKARLACSAPNWQLYFNQLQAM

490 500 510 520 530 540

— I — I — . i . , . . | — I — | — i , — i — t — i — i — T i

^{MOL5a Q}JggΘ^^^^^^^^^^^^^^^^^^^^S^^^^^E^EΞffiϊΞiϊiSΞl.E.S ⁵⁴° MOL5b ^^^S^^SS^β^^^^BS^^^^I^SB^^^S^^^^^^^^SBmm 540 OL5C ^ffltS^^^m^^^^^^^^^ffl^^^^^^^S^^^^^^^^ffl^rø 540 O 5 ^™SSHSκ(8ffij^^^^^^S*^^^^^^^^^^^^^^^^^^^^fflfiπffi 520

MOLΞe ^^^^^^^S^Rj^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^gffi 522

MO 5f laSmSj-fiHJISBziffiSffaBiB 522

610 620 630 640 650 660

— 1 — I — 1 — 1 — I ■ - - - 1 — ] — I — 1 — ] — j — I

MOL5a ^^^^ggrøπffl^^^g^^S^^^^^^^^^^^^^^^^^^^gAAP E 660

MOL5b ^ffl^^nffl^^^^^^^^ffl^^^^^^^^^^^H^^^^^^^gARAPLE 660

MOL5C ^ffls^^g^^^^βffla^gg^^^^^^^^^^^^^^^^^^^BfflARAPLE 660

MOL5d ^fflBrø^^^^^βfflHffiKj^^^^fflgg^^^^^^^^^^ffl-- 634

MOL5e ^^^^^^S^^^^S^^^^^^^^Hϊ^^^^^^^^^^^^^^fflE 638 OL5f fljSBiB3-lSal^BCTBfi3iS3SiBSH^ 638

670 680 690 700 710 720

MOL5a NLGLVWLAWALGAVCLVLLLLVLSLRRRLREELEKGAKATERTLVYPLELPKEPTSPPF 720 OL5b NLGLVWLAWALGAVCLVLLLLvLSLRRRLREELEKGAKATERTLVYPLELPKEPTSPPF 720

MOL5C NLGLvWLAWALGAVCLvLLLLVLSLRRRLREELEKGAKATERTLVYPLELPKEPTSPPF 720

MOL5d 634

MOL5e 638

MOL5f 638

730 740 750 760 770 780

MOL5a RPCPEPDEKLWDPVGYYYSDGSLKIVPGHARCQPGGGPPSPPPGIPGQPLPSPTRLHLGG 780 MOL5b RPCPEPDEKLWDPVGYYYSDGSLKIVPGHARCQPGGGPPSPPPGIPGQPLPSPTRLHLGG 780

MOL5C RPCPEPDEKLWDPVGYYYSDGSLKIVPGHARCQPGGGPPSPPPGIPGQPLPSPTRLHLGG 780 OL5d . 634

MOL5e 638

MOL5f 638

790 800 810 820 830

MOL5a GRNSNANGYVRLQLGGEDRGGLGHPLPELADELRRKLQQRQPLPDSNPEESSV 833

MOL5b GRNSNANGYVRLQLGGEDRGGLGHPLPELADELRRKLQQRQPLPDSNPEESSV 833

MOL5C GRNSNANGYVRLQLGGEDRGGLGHPLPELADELRRKLQQRQPLPDSNPEESSV 833

MOL5d 634

MOL5e 638

MOL5f 638

MOL5a also has homology to other proteins as shown in BLAST alignment results in Table 5P

This information is presented graphically in the multiple sequence alignment given in Table 5Q(with MOL5a being shown on line 1, and MOL5b on line 2) as a ClustalW analysis comparing MOL5 with related protein sequences. Table 5QInformation for the ClustalW proteins:

1) MOL5a (SEQ ID N0:14)

2) M0L5b (SEQ ID NO: 16)

3) gi] 12698023 |dbj |BAB21830.l| (AB051526) KIAA1739 protein [Homo sapiens] (SEQ ID NO:46)

4) gi I 8134699 | sp | Q641511 SM4C_M0USE SEMAPHORIN 4C PRECURSOR (SEMAPHORIN I) (SEMA I) (SEMAPHORIN C-LIKE1) (M-SEMA F) (SEQ ID N0:47)

5) gi I 8923346 I ref |NP_060259.11 sema domain, immunoglobulin domain (Ig) , transmembrane domain TM; cytokeratin 14; adipocyte-derived leucine aminopeptidase; hypothetical protein MGC10851; hypothetical protein FLJ14662; sphingomyelin phosphodiesterase- 1, acid lysosomal; Pro-platelet ba> (SEQ ID NO:48)

6) gi| 13633937|sp|Q9NTN9|SM4G_HUMAN SEMAPHORIN 4G PRECURSOR (SEQ ID

NO:49)

MOL5b and MOL5c share close homology to each other and therefore to other proteins as is shown in the BLAST alignment in Table 5R

Table 5R BLAST alignment between MOL5b and MOL5c

10 20 30 40 50

MOLSb

MOL5c TGCTGCGGGCCCCTCTGGTTTGCTTTCTCTGGCTGTGATTTCTGACCATG 60 70 80 90 100

MOL5b CAGAGCCGGGGCGTGC

MOL5C TCTTTTCCCTCAGCAGGACAGCTGGCCTGAAGCg CAGAGCCGGGGCGTGC

110 120 130 140 150

MOL5b MOL5C GCCATGGCCCCACACTGGGCTGTCTGGCTGCTGGCAGCAAGGCTGTGGGG

160 170 180 190 200

MOL5b CCTGGGCATTGGGGCTGAGGTGTGGTGGAACCTTGTGCCGCGTAAGACAG MOL5C CCTGGGCATTGGGGCTGAGGTGTGGTGGAACCTTGTGCCGCGTAAGACAG

210 220 230 240 250

MOLSb TGTCTTCTGGGGAGCTGGCCACGGTAGTACGGCGGTTCTCCCAGACCGGC MOL5C TGTCTTCTGGGGAGCTGGCCACGGTAGTACGGCGGTTCTCCCAGACCGGC

260 270 280 290 300

MOL5b MOL5C TCCAGGACTTCCTGACACTGACGCTGACGGAGCCCACTGGGCTTCTGT

310 320 330 340 350

..I ....I ....I....I ....I ....I ....I ....I ....I

MOL5b CGTGGGCGCCAGGGACCATGCCTCTGCACTGGGCGTCCCTGTGTTGCTGC MOL5C

360 370 380 390 400

MOL5b MOL5C

410 - 420 430 440 450

MOL5b vTCCAGAAAGGGAAGAACAACCAGACCGAGTGCTTCAACTTCATCCGCTT MOL5C TCCAGAAAGGGAAGAACAACCAGACCGAGTGCTTCAACTTCATCCGCTT

460 470 480 490 500

MOL5b MOL5C

510 520 530 540 550

MOL5b TCCAGCCCAAGTGCACCTACGTCAACATGCTCACCTTCACTTTGGAGCAl MOL5C TCCAGCCCAAGTGCACCTACGTCAACATGCTCACCTTCACTTTGGAGCAI

560 570 580 590 600

MOL5b GGAGAGTTTGAAGATGGGAAGGGCAAGTGTCCCTATGACCCAGCTAAGGG MOL5C GGAGAGTTTGAAGATGGGAAGGGCAAGTGTCCCTATGACCCAGCTAAGGG

610 620 630 640 650

91 MOL5b CCATGCTGGCCTTCTTGTGGATGGTGAGCTGTACTCGGCCACACTCAA MOLΞc

710 720 730 740 750

MOLSb XCCATGAAGACAGAGTACCTGGCCTTTTGGCTCAACGAACCTCACTTTGT MOL5C ΓCCATGAAGACAGAGTACCTGGCCTTTTGGCTCAACGAACCTCACTTTGT

760 770 780 790 800

MOL5b GGCTCTGCCTATGTACCTGAGAGTGTGGGCAGCTTCACGGGGGACGACG MOL5C GGCTCTGCCTATGTACCTGAGAGTGTGGGCAGCTTCACGGGGGACGACG

810 820 830 840 850

MOLΞb CAAGGTCTACTTCTTCTTCAGGGAGCGGGCAGTGGAGTCCGACTGCTAT MOL5C CAAGGTCTACTTCTTCTTCAGGGAGCGGGCAGTGGAGTCCGACTGCTAT

860 870 880 890 900

MOL5b GCCGAGCAGGTGGTGGCTCGTGTGGCCCGTGTCTGCAAGGGCGATATGGG MOL5c 3CCGAGCAGGTGGTGGCTCGTGTGGCCCGTGTCTGCAAGGGCGATATGGG

910 920 930 940 950

MOL5b GGGCGCACGGACCCTGCAGAGGAAGTGGACCACGTTCCTGAAGGCGCGGC MOL5C GGGCGCACGGACCCTGCAGAGGAAGTGGACCACGTTCCTGAAGGCGCGGC

960 970 980 990 1000

MOL5b TGGCATGCTCTGCCCCGAACTGGCAGCTCTACTTCAACCAGCTGCAGGCG MOL5C TGGCATGCTCTGCCCCGAACTGGCAGCTCTACTTCAACCAGCTGCAGGCG

1010 1020 1030 1040 1050

I ....| .... I I I ....I

MOL5b MOL5C TGCACACCCTGCAGGACACCTGCTGGCACAACACCACCTTCTTTGGGGT

1110 1120 1130 1140 1150

MOL5b GTTGGAAGAGATCCAGCGGGTGTTTGAGGGCCCCTATAAGGAGTACCAl MOL5C GTTGGAAGAGATCCAGCGGGTGTTTGAGGGCCCCTATAAGGAGTACCAΪ

1160 1170 1180 1190 1200

MOL5b GAGGAAGCCCAGAΛGTGGGACCGCTACACTGACCCTGTACCCAGCCCTCG MOLSc GAGGAAGCCCAGAAGTGGGACCGCTACACTGACCCTGTACCCAGCCCTCG

1210 1220 1230 1240 1250

MOL5b GCCTGGCTCGTGCATTAACAACTGGCATCGGCGCCACGGCTACACCAGCT MOL5C GCCTGGCTCGTSCATTAACAACTGGCATCGGCGCCACGGCTACACCAGCT

1260 1270 1280 1290 1300

MOLSb CCCTGGAGCTACCCGACAACATCCTCAACTTCGTCAAGAAGCACCCGCTG MOL5c CCCTGGAGCTACCCGACAACATCCTCAACTTCGTCAAGAAGCACCCGCTG 1310 1320 1330 1340 1350

MOL5b GGAGGAGCAGGTGGGGCCTCGGTGGAGCCGCCCCCTGCXCGTGAA

MOL5c GGAGGAGCAGGTGGGGCCTCGGTGGAGCCGCCCCCTGCTCGTGAA

1410 1420 1430 1440 1450

MOLSb 3AGCCACCTATACAGTGCTGTTCATTGGCACAGGAGACGGCXGGCTGCT

MOL5c _3_A_G_CC_A_C_CTATACAGTGCTGTTCATTGGCACAGGA6ACGGCTGGCTGCTC

1510 1520 1530 1540 1550

MOL5b GTTTGACCAGGAGCCCATGAGAAGCCTGGTGCTATCTCAGAGCAAGAAGC

MOL5C _G_T__T_T_G_A_C_CAGGAGCCCATGAGAAGCCTGGTGCTATCTCAGAGCAAGAAGC

1610 1620 1630 1640 1650

....1....1_..... I .... I .... I .... I .... I .... I .... I .... I

MOL5b

MOL5c _ T_GC__A_T__G_A_AGTATCGCTCCTGTGCAGACTGTGTCCTCGCCCGGGACCCCT

1710 1720 1730 1740 1750

■..■i....ι....|....)....|....ι....|....ι....|....ι

MOL5b ^_^_l___^_^'^_ξ^-^^- l?^^u^^'^^lS^'^^l^ ^^ MOLΞc _ s___&__m__w mmm m m B xmmwgmswm.

1760 1770 1780 1790 1800

MOL5b

MOL5C GCAACCTCCGTGGCAGTAAGAAAGTCAGGCCCACTCCCAAAAACATCAC

1810 1820 1830 1840 1850

MOL5b GGTGGTGGCGGGCACAGACCTGGTGCTGCCCTGCCACCXCXCCTCCAACT

MOL5c _GGTGGTGGCGGGCACAGACCTGGTGCTGCCCTGCCACCTCTCCTCCAACT

1860 1870 1880 1890 1900

MOL5b TGGCCCAΓGCCCGCTGGACCTTΓGGGGGCCGGGACCΓGCCTGCGGAACAG

MOL5C _ΓGGCCCATGCCCGCTGGACCTTTGGGGGCCGGGACCTGCCTGCGGAACAG

1910 1920 1930 1940 1950

MOL5b CCCGGGTCCTTCCTCTACGATGCCCGGCTCCAGGCCCTGGTTGTGATGGC

MOL5c CCCGGGTCCTTCCTCTACGATGCCCGGCTCCAGGCCCTGGTTGTGATGGC

M0L5O

2010 2020 2030 2040 2050

MOL5b GGGCGCGGCTGGCTGCTGAAGGCTACCTTGTGGCTGTCGTGGCAGGCCCG MOL5C GGGCGCGGCTGGCTGCTGAAGGCTACCTTGTGGCTGTCGTGGCAGGCCCG

2110 2120 2130 2140 2150

MOL5b GCTGGCGGTGGTGGCCCTGGGGGCTGTGTGCCTGGTGCTGCTGCTGCTGG MOL5C GCTGGCGGTGGTGGCCCTGGGGGCTGTGTGCCTGGTGCTGCTGCTGCTGG

2210 2220 2230 2240 2250

MOL5b MOL5C

2360 2370 2380 2390 2400

MOL5C

2410 2420 2430 2440 2450

MOL5b ^^^^^^^I^^^ISSif^GPiSi GGeTTGACGTGGGGGGXGGGCGG MOL5C

2460 2470 2480 2490 2500

MOL5b MOL5C

2560 2570 2580 2590 2600

1........................I

MOLSb MOLSc

2660 2670 2680 2690 2700 MOLSb

MOL5C CTACTTTTGCACAGGCACCAGCTACCTCAGGGACATGGCACGGGCACCTG 2710 2720 2730 2740 27S0

MOL5b

MOL5C CTCTGTCTGGGACAGATACTGCCCAGCACCCACCCGGCCATGAGGACCTG 276^"0 2770 2780 2790 2800

MOLSb

MOL5 C CTCTGCTCAGCACGGGCACTGCCACTTGGTGTGGCTCACCAGGGCACCAG 2810 2820 2830 2840 2850

MOL5b

MOL5C CCTCGCAGAAGGCATCTTCCTCCTCTCTGTGAATCACAGACACGCGGGAC 2S6^"0 2S70 2880 2890 2900

MOL5b

MOL5C CCCAGCCGCCAAAACTTTTCAAGGCAGAAGTTTCAAGATGTGTGTTTGTC 2520 2920 2930 2940 2950

MOL5b

MOL5c TGTATTTGCACATGTGTTTGTGTGTGTGTGTATGTGTGTGTGCACGCGCG 2960 2970 2980 2990 3000

MOL5b

MOLS c TGCGCGCTTGTGGCATAGCCTTCCTGTTTCTGTCAAGTCTTCCCTTGGCC 3010 3020 3030 3040 3050

MOL5b

MOL5c TGGGTCCTCCTGGTGAGTCATTGGAGCTATGAAGGGGAAGGGGTCGTATC 3060 3070 3080 3090 3100

MOL5b -

MOL5c ACTTTGTCTCTCCTACCCCCACTGCCCCGAGTGTCGGGCAGCGATGTACA 3110

MOL5b

MOL5C TATGGAGGTGGG

As used herein, any reference to MOL5 encompasses MOL5a, MOL5b, and MOL5c, unless otherwise indicated.

Table 5Sand 5Tlist the domain descriptions from DOMAIN analysis results against MOL5. The region from amino acid residue 66 through 487 (SEQ ID NO: 14) most probably (E = 3e^~125) contains a Sema domain found in Semaphorins, described above under MOL4, and aligned here in Table 5S The region from amino acid residue 562 through 627 (SEQ ID NO: 14) most probably (E = le^"4) also contains a Sema domain found in Semaphorins, aligned here in Table 5T This indicates that the MOL5 sequence has properties similar to those of other proteins known to contain this domain.

110 120 140 150

MOL5_l - -|TΪEHGEF D|KgκB Pfam | pfam01403

310 320 330 340 350

MOL5_l TgQDTS HNTTFFS 3IBEYQLEE9QP Pfam|pfa 01403 LBPTDNDTDPVLYΪ 3vg FSWKDaNQβj|- _

360 380 390 400

MOL5_l HEEAζβDRHTDPH SISJKWHRRHGYTHS EB Pfam | pfam01403 G -S|3!| P3RGRS

420 430 440 450

MOL5_l 3Bκιn JEEQ SJEJGGJraSRWWSSRRSSΪΪLffiffiKKKKGGTTffiiJi-- -- F FBHHHLLVVAΆHI33BTGT.,BI8A Pfam|pfam01403 SDTΠ HDDVMPlS HHVaiFmGOSGiiSYR WaXA lBaBEAnitiao

(SEQ ID NO : 97 )

Table 5T Domain Analysis of MOL5 gnl I Smart | smart00409, IG, Immunoglobulin

CD-Length = 85 residues, only 79.1% aligned

Score = 42.0 bits (97), Expect = le-04

20 30 50 MOL5 5 gKNlEEVAgTDLvgpgHL§S--IS-L H R|TFG @ D3P[J

Smart | smart00409 §PS3 _SKE@ES !TJ3SSEA@G- --S|S|PPPPPPTTVVTIJS5YYKQ _GK_L|

MOL5_5

Smart I smart 00409

110

M0L5_S LAAEGYLVAffiVAGPS

Smart |smart00409 SSGSASS-GflTLTVL (SEQ ID NO:98)

The protein similarity information, expression pattern, cellular localization, and map location for MOL5 suggest that this Semaphorin 4C-like protein may have important structural and/or physiological functions characteristic ofthe Semaphorin family. These functions include growth cone guidance, axonal pathfindin, and embryonic development. Therefore, the MOL5 nucleic acids and proteins are useful in potential diagnostic and therapeutic applications and as a research tool. These include serving as a specific or selective nucleic acid or protein diagnostic and/or prognostic marker, wherein the presence or amount ofthe nucleic acid or the protein are to be assessed. These also include potential therapeutic applications such as the following: (i) a protein therapeutic, (ii) a small molecule drug target, (iii) an antibody target (therapeutic, diagnostic, drug targeting/cytotoxic antibody), (iv) a nucleic acid useful in gene therapy (gene delivery/gene ablation), (v) an agent promoting tissue regeneration in vitro and in vivo, and (vi) a biological defense weapon.

The MOL5 nucleic acids and proteins have applications in the diagnosis and/or treatment of various diseases and disorders. For example, the compositions ofthe present invention will have efficacy for the treatment of patients suffering from: Rheumatoid arthritis (RA), CNS disorders, Alzheimer, Down syndrome, Schizophrenia, Parkinsons diseases as well as other diseases, disorders and conditions.

MOL5 is a Semaphorin 4C like protein. Semaphorin 4C (S4C, previously called M-SemaF) was recently identified as a brain rich transmembrane member of semaphorin family ofthe vertebrate. In the cytoplasmic domain of S4C there is a proline-rich region suggesting that the cytoplasmic domain may play an important role in Sema4C function. The cytoplasmic domain (cd) of M-SemaF(S4C)-associating protein has been identified with a MW of 75 kDa, named SFAP75, from mouse brain. SFAP75 turned out to be the same as the recently reported neurite-outgrowth-related protein named Norbin. Deletion mutants analyses of S4C and SFAP75 have revealed that the membrane-proximal region of S4Ccd binds to the intermediate region of SFAP75. Western blot and immunohistochemical analyses with anti-Sema4C and anti-SFAP75 antibodies indicated that S4C and SFAP75 were specially enriched in the brain with a similar distribution pattern to each other. These results suggest that S4C interacts with SFAP75 and plays a role in neural function in brain.

Semaphorins are also known to act as chemorepulsive molecules that guide axons during neural development. Sema4C, a group 4 semaphorin, is a transmembrane semaphorin of unknown function. The cytoplasmic domain of Sema4C contains a proline- rich region that may interact with some signaling proteins. It has been demonstrated that Sema4C is enriched in the adult mouse brain and associated with PSD-95 isoforms containing PDZ (PSD-95/DLG/ZO-1) domains, such as PSD-95/SAP90, PSD- 93/chapsinl 10, and SAP97/DLG-1, which are concentrated in the post-synaptic density of the brain. In the neocortex, S4C is enriched in the synaptic vesicle fraction and Triton X- 100 insoluble post-synaptic density fraction. Immunostaining for Sema4C overlaps that for PSD-95 in superficial layers I-IV ofthe neocortex. In neocortical culture, S4C is colocalized with PSD-95 in neurons, with a dot-like pattern along the neurites. Sema4C thus may function in the cortical neurons as a bi-directional transmembrane ligand through interacting with PSD-95.

These materials are further useful in the generation of antibodies that bind immuno-specifically to the novel MOL5 substances for use in therapeutic or diagnostic methods. These antibodies may be generated according to methods known in the art, using prediction from hydrophobicity charts, as described in the "Anti-MOLX Antibodies" section below. The disclosed MOL5 protein has multiple hydrophilic regions, each of which can be used as an immunogen. In one embodiment, a contemplated MOL5 epitope is from about amino acids 30 to 70. In another embodiment, a MOL5 epitope is from about amino acids 100 to 150. In additional embodiments, MOL5 epitopes are from about amino acids 175 to 200, 220 to 450, 550 to 575, 590 to 610, and from about amino acids 675 to 850. These novel proteins can also be used to develop assay systems for functional analysis. MOL6

The disclosed novel kappa casein precursor -like MOL6 nucleic acid of 603 nucleotides (also referred to as GMAC060288_A) is shown in Table 6A. An open reading begins with an ATG initiation codon at nucleotides 31-33 and ends with a TAA codon at nucleotides 574-576. A putative untranslated region upstream from the initiation codon and downstream from the termination codon are underlined in Table 6A, and the start and stop codons are in bold letters.

Table 6A. MOL6 Nucleotide Sequence (SEQ ID NO:19)

TTTTTTTTAAATTTATCTTTAGGTGCAATAATGAAGAGTTTTCTTCTAGTTGTCAATGCCCTGGCATTAACCCTG CCTTTTTTGCTAGTGGAGGTTCAAAACCAGAAACAACCAGCATGCCATGAGAATGATGAAAGACCATTCTATCAG AAAACGTTCACATATGTCCCAATGTATTATGTGCAAAATAGCTATCTTTATTATGGACCCAATTTGTACAAACGT AGACCAGCTATAGCATTAAATAATCAATATGGGCTTCGCACATATTATGCAACCCAAGCTGTAGTTAGGGCACAT GCCCAAATTCCTCAGCGGCAATACCTGCCAAATAGCCACCACACTGTGGTACGTCGCCCAAACCTGCATCCATCA TTTATTGCAATCCCCCCAAAGAAAATTCAGGATAAAATAATCATCCCTACCATCAATACCATTGCTACTGTTGAA CCTACACCAGCTCCTGCCACTGAACCAACGGTGGACAGTGTAATCACTCCAGAAGCTTTTTCAGAGTCCATCATC ACGAGCACCCCTGAGACAACCACAGTTGCAGTTACTCCACCTACGGCATAAAAACACCAAGGAAATATCAAAGAA CAC

The MOL6 protein encoded by SEQ ID NO:20 has 181 amino acid residues, and is presented using the one-letter code in Table 6B (SEQ ID NO:20). The Psort profile for MOL6 predicts that this sequence has a signal peptide and is likely to be localized outside the cell with a certainty of 0.8200. The most likely cleavage site for a peptide is between amino acids 24 and 25: VQN-QK based on the SignalP result. The molecular weight o the MOL6 protein is 20424.3 Daltons.

Table 6B. Encoded MOL6 protein sequence (SEQ ID NO:20).

MKSFLLVTOALALTLPFLLVEVQNQKQPACHENDERPFYQKTFTYVPMYYVQNSYLYYGPNLYKRRPAIALNNQYG LRTYYATQAVVRAHAQIPQRQYLPNSHHTWRRPNLHPSFIAIPPKKIQDKIIIPTINTIATVEPTPAPATEPTVD SVITPEAFSESIITSTPETTTVAVTPPTA

The disclosed nucleic acid sequence has 566 of 586 bases (96 %) identical to a Homo sapiens kappa casein precursor mRNA (GENBANK-ID: ACC: 129004) (E value = 9.8e-¹¹⁶).

The full amino acid sequence of MOL6 was found to have 165 of 182 amino acid residues (90%) identical to, and 168 of 182 residues (92%) positive with, the 182 amino acid residue kappa casein precursor protein from Homo sapiens (ptnr: SWISSPROT- ACC:P07498) (E value = 3.0e-⁸³), 165 of 182 amino acid residues (90%) identical to, and 168 of 182 residues (92%) positive with patp:AAR39351 Recombinant human kappa casein - Homo sapiens having 182 aa (E value = 3.0e-^8j), and 165 of 182 amino acid residues (90%) identical to, and 168 of 182 residues (92%) positive with patp:AAR92150 Human milk kappa-casein having 182 amino acids (E value = 3.0e-^8j).

The global sequence homology (as defined by FASTA alignment with the full length sequence of this protein) is 92.265 % amino acid homology and 91.160% amino acid identity. In addition, this protein contains the following protein domains (as defined by Interpro) at the indicated nucleotide positions: casein_kappa (IPR000117) at amino acid positions 1 to 181.

The full amino acid sequence of MOL6 was found to have homology with several proteins, including those disclosed in the BLASTP data in Table 6C.

This information is presented graphically in the multiple sequence alignment given in Table 6D (with MOL6 being shown on line 1) as a ClustalW analysis comparing MOL6 with related protein sequences.

Table 6D Information for the ClustalW proteins:

1) MOL6 (SEQ ID NO:20)

2) gi I 1705606|sp[P07498 |CASK_HUMAN KAPPA CASEIN PRECURSOR (SEQ ID NO:50)

3) gi I 4885161 j ref |NP_005203.11 casein, kappa [Homo sapiens] (SEQ ID NO:5l)

4) gij 186555 |gb|AAA59456.l| kappa-casein [Homo sapiens] (SEQ ID NO:52)

5) gij 13633560|re |XP_003538.3 | casein, kappa [Homo sapiens] (SEQ ID NO: 53)

6) gi| 2493502 |sp|P79139 |CASK_CAMDR KAPPA CASEIN PRECURSOR (SEQ ID NO:54)

10 20 30 40 50

60 70 80 90 100

Table 6E lists the domain description from DOMAIN analysis results against MOL6. The region from amino acid residue 1 through 1 16 (SEQ ID NO:20) most probably (E = 2e^" ) contains a casein kappa domain found in Kappa casein, aligned here in Table 6E. This indicates that the MOL6 sequence has properties similar to those of other proteins known to contain this domain.

160 170 190

MOL6 S.TEPTVDSVI TPEAFSESI I rHTPETTT A RpPTg Pfam| pfam00997 τ ^, AEPIVSTWTPEAS1EFI I -STPESTTV§VTSTAA (SEQ ID NO : 99)

The above defined information for MOL6 suggests that this kappa casein precursor-like protein may function as a member of a "Kappa Casein Precursor family". Members of this family is found as a nutritional component of human milk. Therefore, the novel nucleic acids and proteins identified here may be useful in potential therapeutic applications implicated in (but not limited to) various pathologies and disorders as indicated below. The potential therapeutic applications for MOL6 include, but are not limited to: protein therapeutic, small molecule drug target, antibody target (therapeutic, diagnostic, drug targeting/cytotoxic antibody), diagnostic and/or prognostic marker, kappa casein precursor therapy (kappa casein precursor delivery/kappa casein precursor ablation), research tools, tissue reKappa Casein Precursor ration in vivo and in vitro of all tissues and cell types composing (but not limited to) those defined here.

The MOL6 nucleic acids and proteins are useful in potential therapeutic applications implicated in nutritional deficiencies. It is used as a nutrient supplement in milk based products to provide a substantial improvement ofthe nutritional and biological value of the formulae, making it closer in similarity to human milk. Kappa casein can also be used as a pharmaceutical and/or other pathologies and disorders. For example, a cDNA encoding the kappa casein precursor-like protein may be useful in kappa casein precursor therapy, and the kappa casein precursor-like protein may be useful when administered to a subject in need thereof. By way of nonlimiting example, the compositions of the present invention will have efficacy for treatment of patients suffering from nutritional deficiencies. MOL6, or fragments thereof, may further be useful in diagnostic applications, wherein the presence or amount ofthe nucleic acid or the protein are to be assessed. These materials are further useful in the generation of antibodies that bind immuno-specifically to the novel MOL6 substances for use in therapeutic or diagnostic methods. These antibodies may be generated according to methods known in the art, using prediction from hydrophobicity charts, as described in the "Anti-MOLX Antibodies" section below. The disclosed MOL6 protein has multiple hydrophilic regions, each of which can be used as an immunogen. In one embodiment, a contemplated MOL6 epitope is from about amino acids 30 to 125. In another embodiment, a MOL6 epitope is from about amino acids 140 to 160. These novel proteins can also be used to develop assay systems for functional analysis.

MOL7 A novel nucleic acid encoding a human Rh type B glycoprotein -like-protein

MOL7 was identified by TblastN using CuraGen Corporation's sequence file for MOL7 probes or homologs, and run against the Genomic Daily Files made available by GenBank. The disclosed novel MOL7 nucleic acid of 1765 nucleotides (also referred to as AF193808A) is shown in Table 7A. An open reading frame begins with an ATG initiation codon at nucleotides 39-41 and ends with a TAA codon at nucleotides 1383-1385. A putative untranslated region upstream from the initiation codon and downstream from the termination codon are underlined in Table 7A, and the start and stop codons are in bold letters.

Table 7A. MOL7 Nucleotide Sequence (SEQ ID NO:21)

AAAGCCTGCGAGCGCCAGCCGAGATCGCATCCCAACCCATGGCCGGGTCTCCTAGCCQCGCCGCGGGCCGGCGACTGC AGCTTCCCCTGCTGTGCCTCTTCCTCCAGGGCGCCACTGCCGTCCTCTTTGCTGTCTTTGTCCGCTACAACCACAAAA CCGACGCTGCCCTCTGGCACCGGAGCAACCACAGTAACGCGGACAATGAATTTTACTTTCGCTACCCAAGTTTCCAGG ACGTGCATGCCATGGTCTTCGTGGGCTTTGACTTCCTCATGGTCTTCCTGCAGCGTTACGGCTTCAGCAGCGTGGGCT TCACCTTCCTCCTGGCCGCCTTTGCCCTGCAGTGGTCCACACTGGTCCAGGGCTTTCTCCACTCCTTCCACGGTGGCC ACATCCATGTTGGCGTGGAGAGCATGATCAATGCTGACTTTTGTGCGGGGGCCGTGCTCATCTCCTTTGGTGCCGTCC TGGGCAAGACCGGGCCTACCCAGCTGCTGCTCATGGCCCTGCTGGAGGTGGTGCTGTTTGGCATCAATGAGTTTGTGC TCCTTCATCTCCTGGGGGTGAGAGTCTGGGGAGGGATTTCTAGGGTTATGTCTAGTACCATGCTGGAGAAGAGCAAGC ACCGCCAGGGCTCCGTCTACCATTCAGACCTCTTCGCCATGATTGGTGGGACCATCTTCCTGTGGATCTTCTGGCCTA GCTTCAATGCTGCACTCACAGCGCTGGGGGCTGGGCAGCATCGGACGGCCCTCAACACATACTACTCCCTGGCTGCCA GCACCCTTGGCACCTTTGCCTTGTCAGCCCTTGTAGGGGAAGATGGGAGGCTTGACATGGTAGTCCACATCCAAAATG CAGCGCTGGCTGGAGGGGTTGTGGTGGGGACCTCAAGTGAAATGATGCTGACACCCTTTGGGGCTCTGGCAGCTGGCT TCTTGGCTGGGACTGTCTCCACGCTGGGGTACAAGTTCTTCACGCCCATCCTTGAATCAAAATTCAAAGTCCAAGACA CATGTGGAGTCCACAACCTCCATGGGATGCCGGGGGTCCTGGGGGCCCTCCTGGGGGTCCTTGTGGCTGGACTTGCCA CCCATGAAGCTTACGGAGATGGGCTGGAGAGTGTGTTTCCACTCATAGCCGAGGGCCAGCGCAGTGCCACGTCACAGG CCATGCACCAGCTCTTCGGGCTGTTTGTCACACTGATGTTTGCCTCTGTGGGCGGGGGCCTTGGAGGTGGGCTCCTGC TGAAGCTACCCTTTCTGGACTCCCCCCCCGACTCCCAGCACTACGAGGACCAAGTTCACTGGCAGGTGGTGCCTGGCG AGCATGAGGATAAAGCCCAGAGACCTCTGAGGGTGGAGGAGGCAGACACTCAGGCCTAACCCACTGCCAGCCCCTGAG AGGACACGCTCCTTTTCGAAGATGCTGACTGGCTGCTACTAGGAAGTTCTTTTTGAGCTCCCATTCCTCCAGCTGCAA GAAGGGAGCCATGAGCCAGAAGGAGGCCCCTTTCCACAGGCAGCGTCTCCACAGGGAGAGGGGCAACAGGAGGCTGGG AAATGGTGGGGAGTGGGGCCGTAACTGGGTACAATAGGGGGAACCTCACCAGATGCCCAACCCGACTGCCCTACCAGC CTGCACATGGGTAGAAGAGGCCAAATTGAGGCACCCAAGTGATCCACTGGCCCCACGTCACACAGTTACAGTGAAGCC CAAGCCAGGCCTGGTTGAGGGTGATAAACGCCACTGTCTTTAAGGAAAA

The MOL7 protein encoded by SEQ ID NO:21 has 448 amino acid residues, and is presented using the one-letter code in Table 7B (SEQ ID NO:22). The SignalP, Psort and/or Hydropathy profile for MOL7 predict that MOL7 has a signal peptide and is likely to be localized at the plasma membrane with a certainty of 0. 6400. The SignalP shows a signal sequence is coded for with the most likely cleavage site being between amino acids 27 and 28: ATA-VL. This is typical of this type of membrane protein. The molecular weight ofthe MOL7 protein is 48304.3 Daltons.

Table 7B. Encoded MOL7 protein sequence (SEQ ID NO:22).

MAGSPSRAAGRRLQLPL C F QGATAVLFAVFVRYNHKTDAAL HRSNHSNADNEFYFRYPSFQDV HAMVFVGFDFLMVF QRYGFSSVGFTFL AAFALQ STLVQGFLHSFHGGHIHVGVESMINADFCAG AV ISFGAVLGKTGPTQL LMA LEW FGINEFV LH LGVRV GGISRVMSSTMLEKSKHRQGSV YHSD FAMIGGTIFL IFWPSFNAALTALGAGQHRTALNTYYS AASTLGTFALSALVGEDGRLDMV VHIQNAALAGGλAAGTSSE M TPFGALAAGF AGTVSTLGYKFFTPILESKFKVQDTCGVHNLHGM PGVLGALLGVLVAGLATHEAYGDG ESVFPLIAEGQRSATSQAMHQLFGLFVTLMFASVGGGLGGGL LLK PFLDSPPDSQHYEDQVH QWPGEHEDKAQRPLRVEEADTQA The nucleic acid sequence of MOL7 was found to have 680 of 815 bases (83 ) identical to a mouse Rh type b glycoprotein mRNA (GENBANK- ID:AF193808|acc:AF193808).

The full amino acid sequence of MOL7 was found to have 363 of 448 amino acid residues (81%) identical to, and 399 of 448 residues (89%) positive with, the 455 amino acid residue mouse RH TYPE B GLYCOPROTEIN (ptnr: SPTREMBL-ACC:Q9QXP1)

The full amino acid sequence of MOL7 was found to have homology with several proteins, including those disclosed in the BLASTP data in Table 7C.

This information is presented graphically in the multiple sequence alignment given in Table 7D (with MOL7 being shown on line 1) as a ClustalW analysis comparing MOL7 with related protein sequences.

Table 7D Information for the ClustalW proteins:

1) OL7 (SEQ ID N0:22)

2) gi I 99668911 ref |NP_065140. h type B glycoprotein [Homo sapiens] (SEQ ID NO: 55)

3) gi |l4346006|gb|AA 15395.1 (AY013268) Rh type B glycoprotein [Pan troglodytes] (SEQ ID NO: 56)

4) gi| 14486159|gb|AAK14651.1 (AY013261) Rh type B glycoprotein [Sus scrofa] (SEQ ID NO: 57)

5) gi| 10946710 I ref |NP_067350.11 Rhesus blood group-associated B glycoprotein; Rh type B glycoprotein [Mus musculus] (SEQ ID NO:58)

6) gi| 1448616l|gb|AAK14652.l| (AY013262) Rh type B glycoprotein [Oryctolagus cuniculus] (SEQ ID NO: 59)

10 20 30 40 50

II

Table 7E lists the domain description from DOMAIN analysis results against MOL7. The region from amino acid residue 25 through 336 (SEQ ID NO:22) most probably (E = le^"'") contains an ammonium transporter domain found in Ammonium transporters, aligned here in Table 7E. This indicates that the MOL7 sequence has properties similar to those of other proteins known to contain this domain.

70 80 90 100

MOL7 auFLMVgLQRWGR 3SVGFT FLIAHFALS Pfam|pfam0090S SGYSIIAHGKSB-1 SGFIGN GfflLfa no 130 140

MO 7 IHSFHGGH- IHVGVE|MINSDFCAGAVLIS G|VJJBKTGPTQ LLMALL Pfam|pfam00909 BFQL FAA-TAITIIIGAVSERIKFSAYCLHSILΠBTLVYPPVAH VWG

210 220 230 240 250

MO 7 QGSVY ϊ|iJϋSSDEL| BISGI IFM SIFBSPSR 3ALT-ΘLGAGQHR-- Pfam|pfam00909 SFT KNEAITP jjjN MLL P| _ιM-l L Π 5FG|FG[| SGSALSADGRARA--

260 270 280 290 300

MO 7 - - -TΘIJSS YSL ,HAASSTTUjIGGTTFFAA !HM 7GEDHR- -LD VAfflIQ OBSAAgESI Pfam|pfam00909 IGGABTAILIHRB iLgjA

370 380 390 400

MOL7 P@VL@AI(LGVI₍V0GJlATHEAYGDGLESVFPLlAEfflQRSATSQ Pfam|pfam00909 DgF ,vB G@I gGIAVGIF@ 2YV

410 440 450

MOL7 AMHQLFGLFVT MFASVHGGLGG£ JKfflPFLDS P PDBQH gDQVHWQ W Pfara|pfam00909 QLGVQLIGIAVILAYAFGVTFII IGiTLG- - RVBEEEIKVGLDVAE

(SEQ ID NO : 100 )

TaqMan Data

Example 2 shows a TaqMan expression profile in 41 normal human tissues and 55 human cancer cell lines. The MOL7 gene is expressed in normal tissues, specifically lung, colon, small intestine, and prostate, and is lost in cancer cell lines.

Example 2 also shows replicate TaqMan expression results in tumor tissues that are often matched with normal adjacent tissue (NAT), as defined by the operating surgeon. The results reveal that the MOL7 human Rh type B glycoprotein is overexpressed in kidney tumors compared with their NAT and normal tissues. Chromosomal localization:

This gene belongs to genomic DNA GenBank AL139130 which maps to chromosome 1.

Tissue expression: MOL7 has been found to be expressed in Renal clear cell carcinoma by EST analysis. Genbank EST AI310325 has 100% identity with novel Rh type B glycoprotein and was obtained from 2 pooled tumors (clear cell type). Kidney, AI925934 has 100% identity with novel Rh type B glycoprotein and was obtained from Kidney. Fetal spleen R83833 and AI022447 have 96% identity to novel Rh type B glycoprotein and were obtained from Fetal spleen. The tissue expression profile of was also determined by TaqMan.

Uses ofthe Compositions of the Invention

The expression pattern, map location and protein similarity information for the MOL7 suggest that this gene may function as "an Rh family" member. Therefore, the MOL7 nucleic acids and proteins are useful in potential therapeutic applications implicated in various pathologies /disorders described and/or other pathologies/disorders

Potential therapeutic uses for MOL7 include: Protein therapeutic, Small molecule drug target, Antibody target (Therapeutic, Diagnostic, Drug targeting/Cytotoxic antibody), Diagnostic and/or prognostic marker, Gene therapy (gene delivery/gene ablation),

Research tools, Tissue regeneration in vitro and in vivo (regeneration for all these tissues and cell types composing these tissues and cell types derived from these tissues) The MOL7 nucleic acids and proteins are useful in potential therapeutic applications implicated in various names of pathologies/disorders described below and/or other pathologies disorders. For example, a cDNA encoding the RH TYPE B GLYCOPROTEIN -like protein may be useful in gene therapy, and the RH TYPE B GLYCOPROTEIN-like protein may be useful when administered to a subject in need thereof. By way of nonlimiting example, the compositions ofthe present invention will have efficacy for treatment of patients suffering from the pathologies described above. The novel nucleic acid encoding MOL7, or fragments thereof, may further be useful in diagnostic applications, wherein the presence or amount ofthe nucleic acid or the protein are to be assessed.

These materials are further useful in the generation of antibodies that bind immuno-specifically to the novel MOL7 substances for use in therapeutic or diagnostic methods. These antibodies may be generated according to methods known in the art, using prediction from hydrophobicity charts, as described in the "Anti-MOLX Antibodies" section below. The disclosed MOL7 protein has multiple hydrophilic regions, each of which can be used as an immunogen. In one embodiment, a contemplated MOL7 epitope is from about amino acids 40 to 80. In another embodiment, a MOL7 epitope is from about amino acids 160 to 190. In additional embodiments, MOL7 epitopes are from about amino acids 175 to 225, 235 to 250, 325 to 345, 360 to 380, and from about amino acids 400 to 450. These novel proteins can also be used to develop assay systems for functional analysis.

MOL8

A novel human Noelin-2-like nucleic acid was identified by TblastN using CuraGen Corporation's sequence file. The disclosed novel MOL8 nucleic acid of 1399 nucleotides (also referred to as SC84366578_A) is shown in Table 8A. An open reading frame begins with an ATG initiation codon at nucleotides 14-16 and ends with a TAG codon at nucleotides 1391-1393. A putative untranslated region downstream from the termination codon are underlined in Table 8 A, and the start and stop codons are in bold letters.

14 Table 8A. MOL8 Nucleotide Sequence (SEQ ID NO:23)

TGTTTTACTTGAAATGCTACAAACCAACACTCTTTTTATCCTAAAACAGGAGTCTGTGTTTTATGTTTCCCTTTGG TTTCCTCAGACTCAGATTAGTCCTAAAGAAGGGTGGCAGGTGTACAGCTCAGCTCAGGATCCTGATGGGCGGTGCA TTTGCACAGTTGTTGCTCCAGAACAAAACCTGTGTTCCCGGGATGCCAAAAGCAGGCAACTTCGCCAACTACTGGA AAAGGTACAGAACATGTCCCAGTCTATTGAAGTCTTAAACTTGAGAACTCAGAGAGATTTCCAATATGTTTTAAAA ATGGAAACCCAAATGAAAGGGCTGAAGGCAAAATTTCGGCAGATTGAAGATGATCGAAAGACACTTATGACCAAGC ATTTTCAGCAGGAGTTGAAAGAGAAAATGGACGAGCTCCTGCCTTTGATCCCCGTGCTGGAACAGTGCAAAACAGA TGCTAAGTTCATCACCCAGTTCAAGGAGGAAATAAGGAATCTGTCTGCTGTCCTCACTGGTATTCAGGAGGAAATT GGTGCCTATGACTACGAGGAACTACACCAAAGAGTGCTGAGCTTGGAAACAAGACTTCGTGACTGCATGAAAAAGC TATGTGGCAAACTGATGAAAATCACAGGCCCAGTTACAGTCAAGACATCTGGAACCCGATTTGGTGCTTGGATGAC AGACCCTTTAGCATCTGAGAAAAACAACAGAGTATGGTACATGGACAGTTATACTAACAATAAAATTGTTCGTGAA TACAAATCAATTGCAGACTTTGTCAGTGGGGCTGAATCAAGGACATACAACCTTCCTTTCAAGTGGGCAGGAACTA ACCATGTTGTCTACAATGGCTCACTCTATTTTAACAAGTATCAGAGTAATATCATCATCAAATACAGCTTTGATAT GGGGAGAGTGCTTGCCCAACGAAGCCTGGAGTATGCTGGTTTTCATAATGTTTACCCCTACACATGGGGTGGATTC TCTGACATCGACCTAATGGCTGATGAAATCGGGCTGTGGGCTGTGTATGCAACTAACCAGAATGCAGGCAATATTG TCATCAGCCAACTTAACCAAGATACCTTGGAGGTGATGAAGAGCTGGAGCACTGGCTACCCCAAGAGAAGTGCAGG GGAATCTTTCATGATCTGTGGGACACTGTATGTCACCAACTCCCACTTAACTGGAGCCAAGGTGTATTATTCCTAT TCCACCAAAACCTCCACATATGAGTACACAGACATTCCCTTCCATAACCAATACTTTCACATATCCATGCTTGACT ACAATGCAAGAGATCGAGCTCTCTATGCCTGGAACAATGGCCACCAGGTGCTGTTCAATGTCACCCTTTTCCATAT CATCAAGACAGAGGATGACACATAGGCAAAT

The MOL8 protein encoded by SEQ ID NO:23 has 459 amino acid residues, and is presented using the one-letter code in Table 8B (SEQ ID NO:24). The SignalP, Psort and/or Hydropathy profile for MOL8 predict that MOL8 has no signal peptide and is likely to be localized at the microbody (peroxisome) with a certainty of 0.5616. The molecular weight ofthe MOL8 protein is 53275.2 Daltons.

Table 8B. Encoded MOL8 protein sequence (SEQ ID NO:24).

MLQTNTLFILKQESVFYVSLWFPQTQISPKEGWQVYSSAQDPDGRCICTWAPEQNLCSRDAKSRQLRQLLEKVQN MSQSIEVLNLRTQRDFQYVLKMETQMKGLKAKFRQIEDDRKTLMTKHFQQELKEKMDELLPLIPVLEQCKTDAKFI TQFKEEIRNLSAVLTGIQEEIGAYDYEELHQRVLSLETRLRDCMKKLCGK MKITGPVTVKTSGTRFGAWMTDPLA SEKNNRV YMDSYT NKIVREYKSIADFVSGAESRTYNLPFKWAGTNHVVY GSLYFNKYQSNIIIKYSFDMGRVL AQRSLEYAGFH VYPYT GGFSDIDLMADEIGLWAVYATNQNAGNIVISQLNQDTLEVMKS STGYPKRSAGESFM ICGTLYVTNSHLTGAKVYYSYSTKTSTYEYTDIPFHNQYFHISMLDYNARDRALYAWNNGHQVLFNVTLFHIIKTE DDT

The nucleotide sequence of MOL8 has 889 of 1286 bases (69%) identical to a Gallus gallus NOELIN-2 mRNA (GENBANK- ID: AF239804). The full amino acid sequence ofthe protein ofthe invention was found to have 288 of 448 amino acid residues (64%) identical to, and 367 of 448 residues (80%>) positive with, the 457 amino acid residue NOELIN-2 protein from Gallus gallus (Chicken) (ptnr:SPTREMBL-ACC: AAF43715), and 439 of 459 amino acid residues (95%>) identical to, and 442 of 459 residues (96%) positive with, the 458 amino acid residue patp:AAB74696 Human membrane associated protein MEMAP-2.

The global sequence homology (as defined by FASTA alignment with the full length sequence of this protein) is 74%> amino acid homology and 65% amino acid identity. In addition, this protein contains the following protein domain (as defined by Pfam) at the indicated nucleotide positions: Olfactomedin-like domain (PF02191) at amino acid positions 201 to 451.

The full amino acid sequence of MOL8 was found to have homology with several proteins including those disclosed in the BLASTP data in Table 8C.

Homology between MOL8 and other proteins are presented graphically in the multiple sequence alignment given in Table 8D (with MOL8 being shown on line 1) as a ClustalW analysis comparing MOL8 with related protein sequences.

Table 8D. Information for the ClustalW proteins:

1) MOL8 (SEQ ID NO : 24 )

2) gi |3024210|sp|Q62609|NOEl_RAT NOELIN PRECURSOR (NEURONAL OLFACTOMEDIN- RELATED ER LOCALIZED PROTEIN) (PANCORTIN) (1B426B) (SEQ ID NO: 60)

3) gi I 13124385|sp|Q9IAK4|NOEl__CHICK NOELIN PRECURSOR (NEURONAL OLFACTOMEDIN-RELATED ER LOCALIZED PROTEIN) (PANCORTIN) (SEQ ID NO: 61)

4) gi I 9506929 |ref [NP_062371.11 olfactomedin related ER localized protein [Mus musculus] (SEQ ID NO: 62)

5) gi|7248902|gb|AAF43715.l|AF239804_l (AF239804) NOELIN-2 [Gallus gallus] (SEQ ID NO: 63)

6) gi I 2143875 |pir I 1173636 neuronal olfactomedin-related ER localized protein - rat (SEQ ID NO: 64)

gi|3024210| JSAGEAFIICGTLYVTNGYSGGTKVHYAYQTNASTYEYIDIPFQNKYSHI gijl3124385| iSAGEAFIICGTLYVTNGYSGGTKVHYAYQTNASTYEYIDIPFQNKYSHI gi|9506929| ΪSAGEAFIICGTLYVTNGYSGGTKVHYAYQTNASTYEYIDIPFQNKYSHI gi|7248902| vSAGEAFIICGTLYVTNGYSGGTKVHYAYQTNASTYEYIDIPFQNKYSHI gi|2143875| vSAGEAFIICGTLYVTNGYSGGTKVHYAYQTNASTYEYIDIPFONKYSHI

460 470 480

MOL8 ^A itMiMvl-lFitJ-i^'ji-taii Si:IHKTEDDT gi|3024210| SM DYNPKDRALYAWNNGHQULYNVTLFHVIRSDEI gi|l3124385] SMLDYNPKDRALYAWNNGHQ jLYNVTLFHVIRSDEI gi I 9506929| SMLDYNPKDRALYAWNNGHQ JLYNVTLFHVIRSDEI gi|7248902| SMLDYNPKDRALYAWNNGHQ JLYNVTLFHVIRSDEI gij 2143875 j SMLDYNPKDRALYAWNNGHO 1LYNVTLFHVIRSDEI

Table 8E lists the domain description from DOMAIN analysis results against MOL8. The region from amino acid residue 201 through 457 (SEQ ID NO:24) most probably (E = 4e^~83) contains a Olfactomedin-like domain, aligned in Table 8E. This indicates that the MOL8 sequence has properties similar to those of other proteins known to contain this domain.

Table 8E. Domain Analysis of MOL8 gnl I Smart] smart00284, OLF, Olfactomedin-like domains

CD-Length = 257 residues, 100.0% aligned

Score = 308 bits (789), Expect = 4e-85

10 50

MOL8 g 3κκggMMκRBττGj3>SivlciB5lGτ RFwawMTiaSHlAS E - Ei - NNRVJSiaBbs Yil - - smart | smartoo284 ia gπGiglAflGHRsSκiSBiBr,o^ κ-WΑYKsιew';ιaικlBMwM τl5- κsrιYMBlpτ,

160 170 180 190 200

MOL8 JQDHjEVMKS S|SSΠjjGGBHPPg^GES

Smart | smart00284 JSNI IMBKIBI] ΓIIHSN

230 240

MOL8 SSSHKHSTYEYTΠU 3HSQ FHB

Smart I smart00284 BDHNΠGKEGHLB SESMSEYS

260 270

MOL8 MAhtlMrf SSiloQBELLFNVTlllFH

Smart I smart00284 ffiϊϊϊSKfS |LLMØHHYYDDIIAAΪΠl5KKPP (SEQ ID NO : IOI )

Uses of the Compositions of the Invention

The above defined information for MOL8 suggests that this Noelin-2-like protein may function as a member of a "Noelin-2 family". This family is involved in neural crest development, and other developmental processes. Therefore, the novel nucleic acids and proteins identified here may be useful in potential therapeutic applications implicated in (but not limited to) various pathologies and disorders as indicated below. The potential therapeutic applications for MOL8 include, but are not limited to: protein therapeutic, small molecule drug target, antibody target (therapeutic, diagnostic, drug targeting/cytotoxic antibody), diagnostic and/or prognostic marker, gene therapy (gene delivery/gene ablation), research tools, tissue regeneration in vivo and in vitro of all tissues and cell types composing (but not limited to) those defined here.

The MOL8 nucleic acids and proteins are useful in potential therapeutic applications implicated in neural crest development in early embryonic stage. For example, a cDNA encoding the Noelin-2-like protein may be useful in gene therapy, and the Noelin-2-like protein may be useful when administered to a subject in need thereof. By way of nonlimiting example, the compositions ofthe present invention will have efficacy for treatment of patients suffering from primary open-angle glaucoma (POAG), and bone disorders, hematopoietic disorders, neuro-developmental disorders, cancer, autoimmune disorders, psychiatric disorders. The novel nucleic acid encoding MOL8, or fragments thereof, may further be useful in diagnostic applications, wherein the presence or amount ofthe nucleic acid or the protein are to be assessed.

These materials are further useful in the generation of antibodies that bind immuno-specifically to the novel MOL8 substances for use in therapeutic or diagnostic methods. These antibodies may be generated according to methods known in the art, using prediction from hydrophobicity charts, as described in the "Anti-MOLX Antibodies" section below. The disclosed MOL8 protein has multiple hydrophilic regions, each of which can be used as an immunogen. In one embodiment, a contemplated MOL8 epitope is from about amino acids 20 to 50. In another embodiment, a MOL8 epitope is from about amino acids 50 to 125. In additional embodiments, MOL8 epitopes are from about amino acids 140 to 210, 225 to 320, 350 to 375, and from about amino acids 380 to 440. These novel proteins can also be used to develop assay systems for functional analysis. MOL9 or Clone 2191999

Clone 2191999 resembles interleukin-17 (IL-17). The Clone 2191999 nucleotide sequence (SEQ ID NO: 135), shown in Table AAA, is 1107 bp in length. This nucleotide sequence has an open reading frame ("ORF") encoding a polypeptide of 178 amino acid residues (represented in Table AAA; SEQ ID NO:136). The start codon is at nucleotides

65-67 and the stop codon is at nucleotides 599-601. The protein of SEQ ID NO.T36 is predicted by the PSORT program to localize extracellularly with a certainty of 0.4037. The program SignalP predicts an N-terminal signal peptide, with the most likely cleavage site between residues 22 and 23, represented by the dash between the amino acids GSQ- EP (i.e., GlySerGln-GluPro).

Table AAA. Sequence of clone 2191999 (IL17_like)

Translated Protein - Nucleotide 65 to 598

1 AATTCGGTACGAGGCTGGGGTTCAGGCGGGCAGCAGCTGCAGGCT 46 GACCTTGCAGCTTGGCGGAATGGACTGGCCTCACAACCTGCTGTT

MetAspTrpProHisAsnLeuLeuP

91 TCTTCTTACCATTTCCATCTTCCTGGGGCTGGGCAGCCAGGAGCC eLeuLeuThrlleSerllePheLeuGlyLeuGlySerGlnGluPr

136 CCAAAAGCAAGAGGAAGGGGCAAGGGCGGCCTGGGCCCTGGCCTG oGlnLysGlnGluGluGlyAlaArgAlaAlaTrpAlaLeuAlaTr

181 GCCTCACCAGGTGCCACTGGACCTGGTGTCACGGATGAAACCGTA pProHisGlnValProLeuAspLeuValSerArgMetLysProTy

226 TGCCCGCATGGAGGAGTATGAGAGGAACATCGAGGAGATGGTGGC rAlaArgMetGluGluTyrGluArgAsnlleGluGluMetValAl 271 CCAGCTGAGGAACAGCTCAGAGCTGGCCCAGAGAAAGTGTGAGGT aGlnLeuArgAsnSerSerGluLeuAlaGlnArgLysCysGluVa

316 CAACTTGCAGCTGTGGATGTCCAACAAGAGGAGCCTGTCTCCCTG lAsnLeuGlnLeuTrpMetSerAsnLysArgSerLeuSerProTr

361 GGGCTACAGCATCAACCACGACCCCAGCCGTATCCCCGTGGACCT pGlyTyrSerlleAsnHisAspProSerArglleProValAspLe

406 GCCGGAGGCACGGTGCCTGTGTCTGGGCTGTGTGAACCCCTTCAC uProGluAlaArgCysLeuCysLeuGlyCysValAsnProPheTh

451 CATGCAGGAGGACCGCAGCATGGTGAGCGTGCCGGTGTTCAGCCA rMetGlnGluAspArgSerMetValSerValProValP eSerGl 496 GGTTCCTGTGCGCCGCCGCCTCTGCCCGCCACCGCCCCGCACAGG nValProValArgArgArgLeuCysProProProProArgThrGl

541 GCCTTGCCGCCAGCGCGCAGTCATGGAGACCATCGCTGTGGGCTG yProCysArgGlnArgAlaValMetGluThrlleAlaValGlyCy

586 CACCTGCATCTTCTGAATCACCTGGCCCAGAAGCCAGGCCAGCAG sThrCysIlePhe (SEQ ID NO: 136)

631 CCCGAGACCATCCTCCTTGCACCTTTGTGCCAAGAAAGGCCTATG 676 AAAAGTAAACACTGACTTTTGAAAGCAAAAAAACCCCAGGAAGCT

721 TCGGCTGGGTTCCAGACACATGGAAAACAGACTTCCTGTGCCAGC

766 GCATGCTGATCCCTTCAGCAGCCGCTTCTCCACCCTTGGGGCTGC

811 TCTCCAGCACCTGGCAGTGTCCAGAGCGGATAGGGGCGCCGTGTT 856 TGGTGAATGAGTGCACAGACGCCTCTAGGGGGAGCCCAAGATCTG

901 CCTCCTGCCTCCCTCTATTATGCCTTCATAGGTGGGTCAGAACAA

946 AGAATTCCTTATCAACCTCCCGGGTCCCCCACTGCCAATCACCCA

991 CCTCCATTCTACCCTCTACAGCTGCCCCTTATCCCCCAAAGTCCT

1036 GAAATTTTGCTTGGGTCACCTGCTCCAGGAGGCAGAGTTCCCATG 1081 AAGGGTATTAAACGTCTACTACACTGC (SEQ ID NO: 135)

IL-17 is a T cell-derived cytokine that may play an important role in the initiation or maintenance ofthe proinflammatory response. Whereas expression of IL-17 is restricted to activated T cells, the IL-17 receptor is found to be widely expressed, a finding consistent with the pleiotropic activities of IL-17. Two human cytokines, IL-17B and IL- 17C are related to IL-17 (approximately 27% amino acid identity; Proc Natl Acad Sci US A 2000, 97(2):773-8). IL-17B mRNA is expressed in adult pancreas, small intestine, and stomach. IL-17C mRNA is not detected by RNA blot hybridization of several adult tissues. No expression of IL-17B or IL-17C mRNA is found in activated T cells. In a survey of cytokine induction, IL-17B and IL-17C stimulate the release of tumor necrosis factor alpha and IL-1 beta from the monocytic cell line THP-1, whereas IL-17 has a small effect in this system. No induction of IL-1 alpha, IL-6, IFN-gamma, or granulocyte colony-stimulating factor is found in THP-1 cells. Fluorescence-activated cell sorter analysis shows that IL-17B and IL-17C bind to THP-1 cells. Conversely, IL-17B and IL- 17C are not active in an IL-17 assay or the stimulation of IL-6 release from human fibroblasts and do not bind to the human IL-17 receptor extracellular domain. These data show that there is a family of IL-17-related cytokines differing in patterns of expression and proinflammatory responses that may be transduced through a cognate set of cell surface receptors. Because Clone 2191999 is highly related to IL-17, by analogy Clone 2191999 may be utilized in assessing patterns of cytokine expression and in proinflammatory responses

In a BLASTX search the nucleotide sequence of SEQ ID NO:l, Clone 2191999 protein is found to be similar to human PRO1031 protein (90%; W09946281-A2, published 16-SEP-1999), an expressed sequence tag. It is also 90% similar to human interIeukin-17D having 180 residues (W09935267-A1 , published 15-JUL-1999).

Human IL-17D-like polypeptides are significantly related to human IL-17 polypeptides. The homology between IL-17 and IL-17D suggests that an IL-17D-like polypeptide, e.g., Clone 2191999, is capable of signaling through cytokine receptors. IL- 17D-like protein can also be used as a therapeutic agent for the treatment of diseases mediated by IL-17D. IL-17D-like polypeptides bind to B cells. It is likely that these polypeptides can be used for targeting compounds to B cells and B cell tumors, and for specific selection of B cell populations.

BLASTX of SEQ ID NO: 135 further shows that Clone 2191999 protein is 90% similar to human embryo derived interleukin related factor I protein (EDIRF I) having 180 residues (WO9932632-A1, published 01-JUL-1999). The EDIRF-like DNA and protein sequences (e.g., Clone 2191999) and their homologues, antibodies (Ab) specific for EDIRF-like protein, and other modulators may be used: (i) in screening and detection assays, e.g. for chromosome mapping, tissue typing or forensic studies; (ii) in diagnosis, prognosis or monitoring clinical trials; and (iii) for treating or preventing EDIRF-like- related diseases (especially immune, hematopoietic, differentiative, developmental or inflammatory disease, including arthritis and psoriasis. The EDIRF-like coding sequence, or its fragments, are also useful as probes and primers (for detecting related sequences and disease-associated mutations, also for mutagenesis), for expressing recombinant EDIRF and as source of antisense, ribozyme and peptide nucleic acids for inhibiting translation of EDIRF-derived mRNA. EDIRF-like protein is used to raise Ab (useful for detecting EDIRF, including forms with aberrant post-translational modification, for affinity purification and therapeutically) and to screen for specific modulators (e.g. peptides or peptidomimetics).

Clone 2191999 is also 90% similar to human inteι eukin-20 (IL-20; WO9903982- Al, published 28-JAN-1999). The Clone 2191999 sequences represent a human interleukin-20-like gene and gene product that may be used, for example, to treat B-cell neoplasms, including chronic lymphocyte leukemia (CLL) and B-lymphocyte leukemia (BLL), and in anticancer and antiviral treatments. Clone 2191999 may be used to treat immunodeficiencies, e.g. in T- and B-lymphocytes_. leukopenia, reduced numbers of leukocytes, immune disorders, e.g. rheumatoid arthritis. Clone 2191999 may also be used to augment the humoral or cellular immune response in vivo to other therapeutic agents coadministered with Clone 2191999, e.g. to enhance the efficacy of viral antigen vaccines, such as HIV. Clone 2191999 may also be useful in immunotherapeutic and anti- inflammation compositions, for the treatment of patients suffering from chemotherapy from bone marrow transplants, to treat corneal damage, keratitis, ulcers, thrombocytopenia, to restore neutrophil and platelet counts in treatment of cancer, to enhance erythropoietic production for treating anemias associated with inflammation, renal failure, AIDS and cancer. Clone 2191999 may be employed to treat hematopoiesis, and to treat sepsis. Agonists and antagonists of Clone 2191999 can also be used.

The protein encoded by SEQ ID NO: 136 is also 90% similar to human Zcyto7, a polypeptide of 180 residues (WO9849310-A1, published 05-NOV-1998), a mammalian cytokine-like factor 7 polypeptide. Therefore, Clone 2191999 may be useful e.g. to promote bone and cartilage growth, e.g. to treat osteoporosis, or in treatment of inflammation, neurodegenerative diseases, and so forth.

Clone 2191999 includes the full length protein disclosed as being encoded by the ORF described herein, as well as any mature protein arising therefrom as a result ofthe removal of a signal peptide. Clone 2191999 also includes all fragments, analogs, homologs and derivatives of Clone 2191999. Thus the proteins ofthe invention encompass both the precursors and active forms of Clone 2191999 protein.

MOL10 or Clone 11753149.0.6 Clone 11753149.0.6 includes a polynucleotide of 1603 bp in length (Table AAB;

SEQ ID NO: 137. The differentially expressed gene fragment used in the identification of this clone was obtained from fetal brain tissue. Expressed fragments are also observed in fetal brain and thalamus. Clone 1 1753149.0.6 includes an ORF encoding a polypeptide of 344 amino acid residues (Table AAB; SEQ ID NO: 138. The ORF contains a predicted N- terminal signal peptide sequence and a C-terminal membrane attachment sequence between residues 327-344. The initiation codon occurs at nucleotides 92-94 and the termination codon at nucleotides 1 124-1126. The PSORT predicts that the polypeptide localizes in the plasma membrane with a certainty of 0.8110. The SignalP program predicts that the encoded polypeptide has a signal peptide, and that the most likely cleavage site occurs between residues 33 and 34, represented by the dash between the amino acids VRS-GD (i.e., ValArgSer-GlyAsp). SIGNALP also predicts additional signal peptidase cleavage sites in the segment between residues 18 and 34. Table AAB. Sequence of Clone 11753149.0.6 Translated Protein - Nucleotide 92 to 1123

l CAAGCTTGAGAGCAACACAATCTATCAGGAAAGAAAGAΆAGAAAΆ 46 AAACCGAACCTGACAAAAAAGAAGAAAAAGAΆGAAGAAAAAAAAT

91 CATGAAAACCATCCAGCCAAAAATGCACAATTCTATCTCTTGGGC

MetLysThrlleGlnProLysMetHisAsnSerlleSerTrpAl 136 AATCTTCACGGGGCTGGCTGCTCTGTGTCTCTTCCAAGGAGTGCC allePheThrGlyLeuAlaAlaLeuCysLeuPheGlnGlyValPr 181 CGTGCGCAGCGGAGATGCCACCTTCCCCAAAGCTATGGACAACGT oValArgSerGlyAspAlaThrPheProLysAlaMetAspAsnVa

226 GACGGTCCGGCAGGGGGAGAGCGCCACCCTCAGGTGCACTATTGA lThrValArgGlnGlyGluSerAlaThrLeuArgCysThrlleAs

271 CAACCGGGTCACCCGGGTGGCCTGGCTAAACCGCAGCACCATCCT pAsnArgValThrArgValAlaTrpLeuAsnArgSerThrlleLe

316 CTATGCTGGGAATGACAAGTGGTGCCTGGATCCTCGCGTGGTCCT uTyrAlaGlyAsnAspLysTrpCysLeuAspProArgValValLe

361 TCTGAGCAACACCCAAACGCAGTACAGCATCGAGATCCAGAACGT uLeuSerAsnThrGlnThrGlnTyrSerlleGluIleGlnAsnVa 406 GGATGTGTATGACGAGGGCCCTTACACCTGCTCGGTGCAGACAGA lAspValTyrAspGluGlyProTyrThrCysSerValGlnThrAs

451 CAACCACCCAAAGACCTCTAGGGTCCACCTCATTGTGCAAGTATC pAsnHisProLysThrSerArgValHisLeuIleValGlnValSe

496 TCCCAAAATTGTAGAGATTTCTTCAGATATCTCCATTAATGAAGG rProLysIleValGluIleSerSerAspIleSerlleAsnGluGl

541 GAACAATATTAGCCTCACCTGCATAGCAACTGGTAGACCAGAGCC yAsnAsnlleSerLeuThrCysIleAlaThrGlyArgProGluPr

586 TACGGTTACTTGGAGACACATCTCTCCCAAAGCGGTTGGCTTTGT oThrValThrTrpArgHisIleSerProLysAlaValGlyPheVa

631 GAGTGAAGACGAATACTTGGAAATTCAGGGCATCACCCGGGAGCA iSerGluAspGluTyrLeuGluIleGlnGlylleThrArgGluGl

676 GTCAGGGGACTACGAGTGCAGTGCCTCCAATGACGTGGCCGCGCC nSerGlyAspTyrGluCysSerAlaSerAsnAspValAlaAlaPr

721 CGTGGTACGGAGAGTAAAGGTCACCGTGAACTATCCACCATACAT oValValArgArgValLysValThrValAsnTyrProProTyrll

766 TTCAGAAGCCAAGGGTACAGGTGTCCCCGTGGGACAAAAGGGGAC eSerGluAlaLysGlyThrGlyValProValGlyGlnLysGlyTh

811 ACTGCAGTGTGAAGCCTCAGCAGTCCCCTCAGCAGAATTCCAGTG rLeuGlnCysGluAlaSerAlaValProSerAlaGluPheGlnTr 856 GTACAAGGATGACAAAAGACTGATTGAAGGAAAGAAAGGGGTGAA pTyrLysAspAspLysArgLeuIleGluGlyLysLysGlyValLy 901 AGTGGAAAACAGACCTTTCCTCTCAAAACTCATCTTCTTCAATGT sValGluAsnArgProPheLeuSerLysLeuIlePhePheAsnVa

946 CTCTGAACATGACTATGGGAACTACACTTGCGTGGCCTCCAACAA lSerGluHisAspTyrGlyAsnTyrThrCysValAlaSerAsnLy

991 GCTGGGCCACACCAATGCCAGCATCATGCTATTTGGTCCAGGCGC sLeuGlyHisThrAsnAlaSerlleMetLeuPheGlyProGlyAl

1036 CGTCAGCGAGGTGAGCAACGGCACGTCGAGGAGGGCAGGCTGCGT aValSerGluValSerAsnGlyThrSerArgArgAlaGlyCysVa

1081 CTGGCTGCCGCCTCTTCTGGTCTTGCACCTGCTTCTCAAATTTTG lTrpLeuProProLeuLeuValLeuHisLeuLeuLeuLysPhe

1126 ATGTGAGTGCCACTTCCCCACCCGGGAAAGGCTGCCGCCACCACC

1171 ACCACCAACACAACAGCAATGGCAACACCGACAGCAACCAATCAG

1216 ATATATACAAATGAAATTAGAAGAAACACAGCCTCATGGGACAGA 1261 AATTTGAGGGAGGGGAACAAAGAATACTTTGGGGGGAAAAGAGTT

1306 TTAAAAAAGAAATTGAAAATTGCCTTGCAGATATTTAGGTACAAT

1351 GGAGTTTTCTTTTCCCAAACGGGAAGAACACAGCACACCCGGCTT

1396 GGACCCACTGCAAGCTGCATCGTGCAACCTCTTTGGTGCCAGTGT

1441 GGGCAAGGGCTCAGCCTCTCTGCCCACAGAGTGCCCCCACGTGGA 1486 ACATTCTGGAGCTGGCCATCCCAAATTCAATCAGTCCATAGAGAC

1531 GAACAGAATGAGACCTTCCGGCCCAAGCGTGGCGCTGCGGGCACT

1576 TTGGTAGACTGTGCCACCACGGCGTGTG

In searches of nucleic acid sequence databases, clone 1 1753149.0.6 resembles rat neurotrimin, a subfamily of differentially expressed neural cell adhesion molecules, to the extent of 84% identity of 1477 bp in a total sequence of 2040 bp (GenBank- ID:RNU16845|acc:U16845; Struyk et al J. Neurosci. 15 (3), 2141-2156 (1995)). Similarities to the additional nucleic acids, described as having similar or analogous properties, were also found, including (1) chicken mRNA for CEPU-1 , an immunoglobulin superfamily molecule expressed by developing cerebellar Purkinje cells (GenBank-ID:GGCEPUl|acc:Z72497, Spaltmann and Brummendorf. Neurosci. 16 (5), 1770-1779 (1996));(2) chicken CEPU gene identified as a neural secreted glycoprotein belonging to the immunoglobulin-like opioid binding cell adhesion molecule (OBCAM) subfamily,(GenBank-ID:GGCEPUS|acc:AJ225897, Kim et al., 1999 Mol. Cells 9 (3), 270-276); and (3) Bovine mRNA for opioid binding protein / cell adhesion molecule OBCAM (GenBank-ID:BTOBCAM|acc:X 12672).

BLASTP search revealed that the polypeptide encoded by clone 1 1753149.0.6 has 31 1 of 336 residues (92%) identical to, and 320 of 336 residues (95%) positive with rat neurotrimin precursor (GP65) having 344 residues (GenBank acc:Q62718). It also has 240 of 337 residues (71%) identical to, and 277 of 337 residues (82%) positive with human opioid binding protein/cell adhesion molecule precursor (OBCAM) having 345 residues (GenBank acc:Ql 4982). Neurotrimin-like and/or OBCAM-like proteins ofthe invention encoded by clone

11753149.0.6 include the full length protein disclosed as being encoded by the ORF described herein, as well as any mature protein arising therefrom as a result ofthe removal of a signal peptide. Clone 1 1753149.0.6 also includes all fragments, analogs, homologs and derivatives of Clone 1 1753149.0.6. Thus the proteins ofthe invention encompass both the precursors and the active forms ofthe neurotrimin-like and/or OBCAM-like proteins. MOL11 or Clone 11753149.0.37

Clone 11753149.0.37 is a variant of clone 1 1753149.0.6, wherein the nucleotide sequence has a longer 5' untranslated region (UTR), but the same open reading frame. Clone 1 1753149.0.37 nucleotide sequence (SEQ ID NO: 139 and the predicted polypeptide sequence encoded therein (SEQ ID NO: 140) are given in Table AAC. The ORF of clone 1 1753149.0.37 extends from nucleotide 501 to nucleotide 1532, in the numbering scheme of SEQ ID NO:XX. The properties ofthe neurotrimin-like or OBCAM-like polypeptide encoded by clone 1 1753149.0.37 are the same as those set forth in the preceding section for clone 1 1753149.0.6. In addition, the long 5' UTR may include control elements and/or response elements that affect the specificity of expression ofthe gene product of clone 1 1753149.0.37 among various tissues, physiological states and pathological conditions.

Table AAC. Sequence of Clone 11753149.0.37 Translated Protein - Frame: 3 - Nucleotide 501 to 1532

1

GCCAGGGAATGCCAGGGGGAAAGGGATTTTCTGATACTCAGAAGA 46 CTCAGAGACTGTCAGTTTAAAAAATGAAAGTAATATAGAAGGGGC 91

AAAGTGGCATTTATCATTCTATCTCTCCAGGCTCCTGTCTCTTTA 136

ATCAGCTAGCCTGATTTGCCCAGTAAATGATTCCTGAGAGTGTGT 181

GTGCGTGTGTGTGTGTGTGTGTGCCCGCGCGCGTGTGTTGTAGCT 226

CTGTCAATCCTTGGATTAGAACCAATGATTGCAGCTTGTAAGAGG 271 GCTGTCCAGGGCCAGATTGTACAATGTGTCTCAGTGCCAGAGTAT

316

GAGTGGAGATAATTACGGAGAAGTCATACTCTCTCACACCCTCGG 361

CTTTCTTGTTGTGTCCTTCAGCAAAACAGTGGATTTAAATCTCCT 406

TGCACAAGCTTGAGAGCAACACAATCTATCAGGAAAGAAAGAAAG 451

AAAAAAACCGAACCTGACAAAAAAGAAGAAAAAGAAGAAGAAAAA 496

AAATCATGAAAACCATCCAGCCAAAAATGCACAATTCTATCTCTT Met ysThrlleGlnProLysMetHisAsnSerlleSerT 541

GGGCAATCTTCACGGGGCTGGCTGCTCTGTGTCTCTTCCAAGGAG rpAlallePheThrGly euAlaAla euCysLeuPheGlnGlyV 586

TGCCCGTGCGCAGCGGAGATGCCACCTTCCCCAAAGCTATGGACA alProValArgSerGlyAspAlaThrPheProLysAlaMetAspA 631

ACGTGACGGTCCGGCAGGGGGAGAGCGCCACCCTCAGGTGCACTA snValThrValArgGlnGlyGluSerAlaThrLeuArgCysThrl

676 TTGACAACCGGGTCACCCGGGTGGCCTGGCTAAACCGCAGCACCA leAspAsnArgValThrArgValAlaTrpLeuAsnArgSerThrl

721

TCCTCTATGCTGGGAATGACAAGTGGTGCCTGGATCCTCGCGTGG leLeuTyrAlaGlyAsnAsp ysTrpCysLeuAspProArgValV 766

TCCTTCTGAGCAACACCCAAACGCAGTACAGCATCGAGATCCAGA alLeuLeuSerAsnThrGlnThrGlnTyrSerlleGluIleGlnA 811

ACGTGGATGTGTATGACGAGGGCCCTTACACCTGCTCGGTGCAGA snValAspValTyrAspGluGlyProTyrThrCysSerValGlnT 856

CAGACAACCACCCAAAGACCTCTAGGGTCCACCTCATTGTGCAAG hrAspAsnHisPro ysThrSerArgValHisLeuIleValGlnV

901 TATCTCCCAAAATTGTAGAGATTTCTTCAGATATCTCCATTAATG alSerProLysIleValGluIleSerSerAspIleSerlleAsnG

946

AAGGGAACAATATTAGCCTCACCTGCATAGCAACTGGTAGACCAG luGlyAsnAsnlleSerLeuThrCysIleAlaThrGlyArgProG 991

AGCCTACGGTTACTTGGAGACACATCTCTCCCAAAGCGGTTGGCT luProThrValThrTrpArgHisIleSerProLysAlaValGlyP 1036

TTGTGAGTGAAGACGAATACTTGGAAATTCAGGGCATCACCCGGG heValSerGluAspGluTyrLeuGluIleGlnGlylleThrArgG 1081

AGCAGTCAGGGGACTACGAGTGCAGTGCCTCCAATGACGTGGCCG luGlnSerGlyAspTyrGluCysSerAlaSerAsnAspValAlaA

1126 CGCCCGTGGTACGGAGAGTAAAGGTCACCGTGAACTATCCACCAT laProValValArgArgValLysValThrValAsnTyrProProT

1171

ACATTTCAGAAGCCAAGGGTACAGGTGTCCCCGTGGGACAAAAGG yrlleSerGluAlaLysGlyThrGlyValProValGlyGlnLysG 1216

GGACACTGCAGTGTGAAGCCTCAGCAGTCCCCTCAGCAGAATTCC lyThr euGlnCysGluAlaSerAlaValProSerAlaGluPheG 1261

AGTGGTACAAGGATGACAAAAGACTGATTGAAGGAAAGAAAGGGG InTrpTyr ysAspAspLysArg euIleGluGlyLysLysGlyV 1306 TGAAAGTGGAAAACAGACCTTTCCTCTCAAAACTCATCTTCTTCA alLysValGluAsnArgProPheLeuSerLysLeuIlePhePheA 1351

ATGTCTCTGAACATGACTATGGGAACTACACTTGCGTGGCCTCCA snValSerGluHisAspTyrGlyAsnTyrThrCysValAlaSerA 1396

ACAAGCTGGGCCACACCAATGCCAGCATCATGCTATTTGGTCCAG snLysLeuGlyHisThrAsnAlaSerlleMetLeuPheGlyProG 1441 GCGCCGTCAGCGAGGTGAGCAACGGCACGTCGAGGAGGGCAGGCT lyAlaValSerGluValSerAsnGlyThrSerArgArgAlaGlyC 1486

GCGTCTGGCTGCCGCCTCTTCTGGTCTTGCACCTGCTTCTCAAAT ysValTrpLeuProProLeuLeuVal euHisLeu euLeuLysP 1531

TTTGATGTGAGTGCCACTTCCCCACCCGGGAAAGGCTGCCGCCAC he 1576

CACCACCACCAACACAACAGCAATGGCAACACCGACAGCAACCAA 1621

TCAGATATATACAAATGAAATTAGAAGAAACACAGCCTCATGGGA 1666

CAGAAATTTGAGGGAGGGGAACAAAGAATACTTTGGGGGGAAAAG 1711 AGTTTTAAAAAAGAAATTGAAAATTGCCTTGCAGATATTTAGGTA

1756

CAATGGAGTTTTCTTTTCCCAAACGGGAAGAACACAGCACACCCG 1801

GCTTGGACCCACTGCAAGCTGCATCGTGCAACCTCTTTGGTGCCA 1846

GTGTGGGCAAGGGCTCAGCCTCTCTGCCCACAGAGTGCCCCCACG 1891

TGGAACATTCTGGAGCTGGCCATCCCAAATTCAATCAGTCCATAG 1936 AGACGAACAGAATGAGACCTTCCGGCCCAAGCGTGGCGCTGCGGG

1981

CACTTTGGTAGACTGTGCCACCACGGCGTGTG

Neurotrimin-like and/or OBCAM-like proteins ofthe invention encoded by clone 1 1753149.0.37 include the full length protein disclosed as being encoded by the ORF described herein, as well as any mature protein arising therefrom as a result ofthe removal of a signal peptide. Clone 1 1753149.0.37 also includes all fragments, analogs, homologs and derivatives of Clone 1 1753149.0.37. Thus the proteins ofthe invention encompass both the precursors and the active forms ofthe neurotrimin-like and/or OBCAM-like proteins.

MOL12 or Clone 3883556

Clone 3883556 includes a polynucleotide of 1228 bp in length (SEQ ID NO: 141, shown in Table AAD. Expression of this sequence is detected in human fetal brain. The polynucleotide of SEQ ID NO: 141 encodes a polypeptide of 166 residues (SEQ ID NO: 142, shown in Table AAD, in an ORF beginning with the initiation codon at nucleotides 529-531 and ending at the stop codon at nucleotides 1027-1029. The PSORT program predicts that the polypeptide is localized extracellularly, with a certainty of 0.37. The SignalP program predicts that the polypeptide has a signal peptide with the most likely cleavage site between residues 16 and 17, represented by the dash between the amino acids SHA-SE (i.e., SerHisAla-SerGlu). Table AAD. Sequence of Clone 3883556

Translated Protein - Nucleotide 529 to 1026 1 GCTCTTCCTGAAGGAAGATCCAGTGGCATATCTCCATGGCTGCCA

46 GACAGAGTAGAGAAATGGAACTTATCGGTGTCTCTTCAGAAGTTT

91 TGTTACAAATATCCAGAAATATTTCTATAATCTAATCAGCAGATT

136 ATGAATATATGCATTAGACTTTAGTTTTGGTGCAATCACATGAAT

181 TCCATTTTGTGGAGTAAGAGGTGACTGGGGTATAGGGTACAACCC 226 ATAGCCATCCATGTTCATCTTTGTTTTGAATATAATTGGCTAGAA

271 GATATACATATATCTATGTAACTTCCTCTAGCATCCTCCAGTATG 316 GAGGCTGCATTAAGACTGCATGAAGGAGAGGGAGAGAAGGGAGAA

361 ACAGAGCAGCTGGACAAGAGGACAGGTATAGGGAATAAGGGAGAA

406 GCCAGTAAGGCAGGAAAGACCCTCCGTGACAAAGGGGCAGGGAAC 451 AGAACTCAAACATTTAATGGCAGGTAACCCAGGTTAGAATGGTAA

496 ATTGAAAGGTGAATATAAAGGGAGAATGGTGAAATGAATTTTCTG

MetAsnPheLeu 541 AAATTAATTGCTGTGTTTATAGTTTTTAGCCATGCATCGGAATCA LysLeuIleAlaValPhelleValPheSerHisAlaSerGluSer

586 CCTCAGGACTCCACTCCCAATCAATTATATATCTGGGGGAGGACC

ProGlnAspSerT rProAsnGlnLeuTyrlleTrpGlyArgThr

631 AAGGCGTTGGTATTTTTCAGAAGCTCCACTGGTGATTCTGACAGC LysAlaLeuValP ePheArgSerSerThrGlyAspSerAspSer

676 ACAGCTAGGATTAAGAAACTGATCAATGGGAACGGCATGCCTGTT ThrAlaArglleLysLysLeuIleAsnGlyAsnGlyMetProVal

721 GCAGAGGAGCTTCCCTGGGAAATGTCACACACAGAACATCAATCT AlaGluGluLeuProTrpGluMetSerHisThrGluHisGlnSer 766 TCCTTCCCCACTCCTGAGATCCCTCATTCTTTGGCACCAGGAACA SerPheProThrProGluIleProHisSerLeuAlaProGlyThr

811 GTTGCAATTAGTAAACCCTGGTTCCCTGCTGTCTCACAAATCGCA ValAlalleSerLysProTrpP eProAlaValSerGlnlleAla

856 AGAGTCCAACGTGTGGATATAAACTTTTGTTCATGGGAGGATCTT ArgValGlnArgValAspIleAsnPheCysSerTrpGluAspLeu 901 TCTCCCAGTGGAAAAGCAACTGGGAAAAGCAGGACACACTGCACA

SerProSerGlyLysAlaThrGlyLysSerArgThrHisCysThr

946 GTGACTGCAGTTTCATCCAATGCCACCACCCATGCAGGCATAAAT ValThrAlaValSerSerAsnAlaThrThrHisAlaGlylleAsn

991 AATGAACATGGATGGGGGAGTCTGGAGCTGCTGAATTGAGGAAGA AsnGluHisGlyTrpGlySerLeuGluLeuLeuAsn 1036 AAGAACACAGAAATTAAAATTCTCACAAAGGTTACCATTAAGCTA

1081 GAGGAAGACCACACCACTGTGTGTCCACAAAGATACAGAGCCAGG 1126 CCGGGTTCAGCCATGCTGGTCATCTGCTCTATATAATACAATTAT 1171 TTAGAGATGGTGGGTAGAGAACAACTACAGAAAAAAAAAAAAAAA 1216 AAAAAAAAAAAAA

BLASTP search revealed a 27% identity, and 41% similarity with ZK899.1 - Caenorhabditis elegans, having 161 aa (ACC:Q23659; Z37140); and a 33% identity, and 47%o similarity with major merozoite surface antigen - Plasmodium berghei yoelii, 641 aa (fragment) (ACC:G 160082). The protein ofthe invention encoded by clone 3883556 includes the full length protein disclosed herein, as well as any mature protein arising therefrom as a result of the removal of a signal peptide. Clone 3883556 also includes all fragments, analogs, homologs and derivatives of Clone 3883556. Thus the proteins ofthe invention encompass both the precursors and the active forms ofthe 3883556 protein. MOL13 or Clone 4301136-1

Clone 4301 136-1 includes a polynucleotide of 1917 bp (SEQ ID NO: 143, as shown in Table AAE. This clone was initially identified in fetal kidney and heart tissue. The polynucleotide of SEQ ID NO: 143 encodes a polypeptide having 160 residues (SEQ ID NO: 144), shown in Table AAE, in an ORF beginning at nucleotides 48-50 and ending with a stop codon at nucleotides 528-530. The PSORT program predicts that the 4301 136- 1 polypeptide localizes extracellularly with a certainty of 0.3700. The SignalP program predicts only a low probability that the polypeptide contains a known signal peptide. If so, the most likely cleavage site for the signal peptide occurs between residues 23 and 24, represented by the dash between the amino acids PWG-GK (i.e., ProTrpGly-GlyLys). Table AAE. Sequence of Clone 4301136-1

Translated Protein - Nucleotide 410 to 889

1 ACGCGTCACATAAAGGAAAGATACGTTTTAATCATCTTTACAAGT 46 GCGTCCTTGTACCTTTCGGGATAACCTGTACTGATTTCTCTGCAG

91 GACCTTTTCAAAGAATCCTCTTCAAGAGAGAAACAAATTTTAGGC

136 TGACGACTTCACGGAGAGGCAGGTTCTGCTGTTGCCAATGAACGA

181 GAACTTTCTACTAGGCTGGCGGCATGCAGAGCCCACGTCTGTCAG 226 CTGCCACCTTCGTAAAGCACACGTTTCACATGCATGAGCTCGAGT

2 1 GGCTAGAACTTCAAAACTGTGCTCAGGTTTTTGTTTTGGAAGTTA 316 TAAAAAAGTTGCTCACAAACAATAGTTATTGCCTTTTATATCTTT

361 TATGTTAGTCTACTAGTCAGCATTCTGCCCAAAATGGAAAGCCAC 406 TCCCATGGGAAGGGAGGGGGTAGCAGCTGGGAGTCTGCTCTTCCA MetGlyArgGluGly¥alAlaAlaGlySerLeuLeuPheGl

451 GCTGGGGGCCCTCCCACCCCCATGGGGAGGAAAGACGTCAAGCTC nLeuGlyAlaLeuProProProTrpGlyGlyLysThrSerSerSe

496 CAGCCACTGGCCCCGGTGGGTCCCAAAGCCCCACCCCTCATGCTC rSerHisTrpProArgTrpValProLysProHisProSerCysSe

541 TCCTCTGGTCACCTCTATTTACGCTCACATGCCCCTTCCTGTCCT rProLeuValThrSerlleTyrAlaHisMetProLeuProValLe

586 TCACCTGCACGTCACCAGCAGGTCCCGCCAACCCCAAATCTATCT uHisLeuHisValThrSerArgSerArgGlnProGlnlleTyrLe 631 GGTGAAAACCTGGAGAACAAGAGCGGAGTCTAAGAGAGATGTAAA uVal ysThrTrpArgThrArgAlaGluSerLysArgAspValAs

676 TGAAAACACAGATCAACAGACACACCAGAAGGGAAGCGTTGTTTC nGluAsnThrAspGlnGlnThrHisGlnLysGlySerValValSe

721 CGCGGGGAAAGGAGATGGAAAGGGGAAGAGAAGTGAAGAATTCTG rAlaGlyLysGlyAspGlyLysGlyLysArgSerGluGluPheCy

766 CGCCCGAAGCTCGGGTTGGTGTTTGCTCAACTGCTTTACTCATTT sAlaArgSerSerGlyTrpCysLeuLeuAsnCysPheThrHisPh

811 TAACCCTTTCACCTATCCTGGGAGAAACCCAGGCTTGTCACCTTT eAsnProPheThrTyrProGlyArgAsnProGlyLeuSerProP 856 TCATGTTGGGTTGTTTGTTTATTGGCCTCTTAAGTGAGAATTGAT eHisValGlyLeuPheValTyrTrpProLeuLys

901 CCGTGAAGGGAAACAGACAGGAGGAGGTCAGATTGCGAATACCTG

946 GGGCTTCCTAGGGTCCAGTGCGGCAGTTACCGCACCTGCCTTCAC 991 CGGTGAACCTTTAGCCAGCTGAACAACCACCAAAGCGCCCTGCAG

1036 AGACAAGTCATCCAGCCCTCTGGCATGTCCCTGGTAGCCCGGGCA

1081 CCAGCCGCTGCGGCTTGTGAGGGGCACCATGCTCCACCCCACGGG

1126 GACCTTCACAGTTGGAAAAAAGAAGAGGAAAAACTAATTCCTTCG

1171 GTAACAGTTTATTTTCATTTTTGGGAAAGGCAAAACCACTACCTG 1216 GAACTCGGTGCCTCCGTGGTTAACTTTCCTATTTTGCTTGTGATT

1261 TAAAGGCTGTTCTGGGTCAGGGGGGAAAAGGTGTCTCCTTCGGTA 1306 GGGAATATATAACGTGGTGATAACCTGTCACTAGGCAGAAGCATC 1351 CACTCTGCAGGGACAGTGGCCCCTCAGGAAAGCCCGCCGCTCCTG 1396 GCCAAGGCCTCTCTGCAGACTCCACGGGGGCTCACCCTCTGCCGT 1441 CAGGCGACTCTGAAATTCCGACATTTCTCCCTTAAAGTCTCAACA 1486 GACACAAGAGAAGTTTCCATCAAGCAAGCACTGACATATTTATAT 1531 TAAAAAATAGTGCAAAATCTCAACATTTATATAAATAACTCTAAA 1576 CCCCTGCTTTGTAATTTTTTTCTTTACAAGGTAATACACACTTTC 1621 TGACTTGGCACTCAAAAATTGCCATTTTTTTCCTCTTCTAGTTCA 1666 GAAAACAACTTTTTTTTTTAATAGGCCTCTTCTAATACAAAAATA 1711 CTCCTGCCCTCGCACATACAGTTTCTCTTATCTTATATATATTTA 1756 TATATATAATATTGCAGATCTTTAAACAAAGGTTTTGTGCAAATA 1801 TGTCTTTAAAGTTAAGTGAAATTATCATAAACAAAAGAAAATAAG 1846 CATTCACGCACGCAGCTCAACTAGAAACAAGAAAGACTACTGTAG 1891 AAATTTTTTTTCTTTTGCCTTCAAGAC

Clone 4301136-1 proteins ofthe invention include the full length protein encoded by the ORF disclosed herein, as well as any mature protein arising therefrom, for example, as a result ofthe removal of a signal peptide. Clone 4301 136-1 also includes all fragments, analogs, homologs and derivatives of Clone 4301 136-1. Thus the proteins ofthe invention encompass both the precursors and the active forms ofthe PCKl-like Clone 4301 136-2 protein. MOL14 or 4301136-2

Clone 4301 136-2 includes a polynucleotide of 1279 bp (SEQ ID NO: 145), shown in Table AAF. This clone was initially isolated from fetal kidney and heart tissues. It is also found in other tissues, including normal adult lung, osteosarcoma, lymph node tissue, prostate gland, thymus gland, and fetal brain.

The polynucleotide of clone 4301 136-2 includes an ORF encoding a polypeptide of 161 residues (SEQ ID NO: 146), shown in Table AAF, with an initiation codon at nucleotides 61-63 and a termination codon at nucleotides 544-546. The PSORT program predicts that this polypeptide localizes extracellularly with a certainty of 0.3700. The SignalP program predicts only a low probability that the polypeptide contains a known signal peptide. If so the most likely cleavage site occurs between residues 23 and 24, represented by the dash between the amino acids PWG-GK (i.e., ProTrpGly-GlyLys). Table AAF . Sequence of Clone 4301136 -2

Translated Protein - Nucleotide 410 to 892

1 ACGCGTCACATAAAGGAAAGATACGTTTTAATCATCTTTACAAGT

46 GCGTCCTTGTACCTTTCGGGATAACCTGTACTGATTTCTCTGCAG 91 GACCTTTTCAAAGAATCCTCTTCAAGAGAGAAACAAATTTTAGGC

136 TGACGACTTCACGGAGAGGCAGGTTCTGCTGTTGCCAATGAACGA 181 GAACTTTCTACTAGGCTGGCGGCATGCAGAGCCCACGTCTGTCAG

226 CTGCCACCTTCGTAAAGCACACGTTTCACATGCATGAGCTCGAGT

271 GGCTAGAACTTCAAAACTGTGCTCAGGTTTTTGTTTTGGAAGTTA

316 TAAAAAAGTTGCTCACAAACAATAGTTATTGCCTTTTATATCTTT 361 TATGTTAGTCTACTAGTCAGCATTCTGCCCAAAATGGAAAGCCAC

406 TCCCATGGGAAGGGAGGGGGTAGCAGCTGGGAGTCTGCTCTTCCA MetGlyArgGluGlyValAlaAlaGlySerLeuLeuPheGl 451 GCTGGGGGCCCTCCCACCCCCATGGGGAGGAAAGACGTCAAGCTC nLeuGlyAlaLeuProProProTrpGlyGlyLysThrSerSerSe

496 CAGCCACTGGCCCCGGTGGGTCCCAAAGCCCCACCCCTCATGCTC rSerHisTrpProArgTrpValProLysProHisProSerCysSe

541 TCCTCTGGTCACCTCTATTTACGCTCACATGCCCCTTCCTGTCCT rProLeuValThrSerlleTyrAlaHisMetProLeuProValLe

586 TCACCTGCACGTCACCAGCAGGTCCCGCCAACCCCAAATCTATCT uHisLeuHisValThrSerArgSerArgGlnProGlnlleTyrLe

631 GGTGAAAACCTGGAGAACAAGAGCGGAGTCTAAGAGAGATGTAAA uValLysThrTrpArgThrArgAlaGluSer ysArgAspValAs 676 TGAAAACACAGATCAACAGACACACCAGAAGGGAAGCGTTGTTTC nGluAsnThrAspGlnGlnThrHisGlnLysGlySerValValSe

721 CGCGGGGAAAGGAGATGGAAAGGGGAAGAGAAGTGAAGAATTCTG rAlaGlyLysGlyAspGlyLysGlyLysArgSerGluGluPheCy

766 CGCCCGAAGCTCGGGTTGGTGTTTGCTCAACTGCTTTACTCATTT sAlaArgSerSerGlyTrpCysLeuLeuAsnCysP eThrHisPh

811 TAACCCTTTCACCTATCCTGGGAGAAACCCAGGCTTGTCACCTTT eAsnProPheThrTyrProGlyArgAsnProGlyLeuSerProP

856 TCATGTTGGGTTGTTTATTGGCCTCTTAAGTGAGAATTGATCCGT eHisValGlyLeuPhelleGlyLeuLeuSerGluAsn 901 GAAGGGAAACAGACAGGAGGAGGTCAGATTGCGAATACCTGGGGC

946 TTCCTAGGGTCCAGTGCGGCAGTTACCGCACCTGCCTTCACCGGT

991 GAACCTTTAGCCAGCTGAACAACCACCAAAGCGCCCTGCAGAGAC

1036 AAGTCATCGAGCCCTCTGGCATGTCCCTGGTAGCCCGGGCACCAG

1081 CCGCTGCGGCTTGTGAGGGGCACCATGCTCCACCCCACGGGGACC 1126 TTCACAGTTGGAAAAAAGAAGAGGAAAAACTAATTCCTTCGGTAA

1171 CAGTTTATTTTCATTTTTGGGAAAGGCAAAACCACTACCTGGAAC

1216 TCGGTGCCTGNGANNTCTTANNTNCTNNCTNAGNCNNATNNGNNA

1261 NNNNTNNNNNANNCTTNNA Clone 4301136-2 includes the full length protein encoded by the ORF disclosed herein, as well as any mature protein arising therefrom, for example, as a result ofthe removal of a signal peptide. Clone 4301136-2 also includes all fragments, analogs, homologs and derivatives of Clone 4301136-2. Thus the proteins ofthe invention encompass both the precursors and the active forms of Clone 4301136-2 protein. MOLl 5 or 4324229

Clone 4324229 includes a polynucleotide of 1689 bp (SEQ ID NO: 147), shown in Table AAG. This clone is shorter in both the 5' and 3' directions than the nucleotide sequence of clone 4324229-2 disclosed in the next section. It also is closely related to the nucleotide sequence of clone AC012614-1.0.123 disclosed below. This sequence was originally identified in lymph node. The Clone 4324229 polypeptide has 316 amino acid residues (SEQ ID NO: 148), represented in Table AAG, and is encoded by an ORF beginning at nucleotides 199-201 of SEQ ID NO: 147, with a termination codon at nucleotides 1 147-1 149. The PSORT program predicts that the polypeptide localizes to the mitochondrial matrix space with a certainty of 0.4433. The SignalP program predicts that this sequence most likely has no known signal sequence. SignalP does predict, however, that if a signal sequence is present, the most likely cleavage site occurs between residues 18 and 19, represented by the dash between the amino acids TRL-QP (i.e., TryArgLeu- GlnPro). Table AAG. Sequence of Clone 4324229.

Translated Protein - Nucleotide 199 to 1146

1 TAGAATTCAGCGGCCGCTTAATTCTAGAACGAATGCCAGTGCCTG 46 GAGGCATGCAGGCCCAGCTACGTGCCTGTGTGCGGCTCTGATGGG

91 AGGTTTTATGAAAACCACTGTAAGCTCCACCGTGCTGCTTGCCTC

136 CTGGGAAAGAGGATCACCGTCATCCACAGCAAGGACTGTTTCCTC

181 AAAGGTGACACGTGCACCATGGCCGGCTACGCCCGCTTGAAGAAT MetAlaGlyTyrAlaArgLeuLysAsn

226 GTCCTTCTGGCACTCCAGACCCGTCTGCAGCCACTCCAAGAAGGA ValLeuLeuAlaLeuGlnThrArgLeuGlnProLeuGlnGluGly 271 GACAGCAGACAAGACCCTGCCTCCCAGAAGCGCCTCCTGGTGGAA AspSerArgGlnAspProAlaSerGlnLysArgLeuLeuValGlu

316 TCTCTGTTCAGGGACTTAGATGCAGATGGCAATGGCCACCTCAGC SerLeuPheArgAspLeuAspAlaAspGlyAsnGlyHisLeuSer

361 AGCTCCGAACTGGCTCAGCATGTGCTGAAGAAGCAGGACCTGGAT SerSerGluLeuAlaGlnHisValLeuLysLysGlnAspLeuAsp

406 GAAGACTTACTTGGTTGCTCACCAGGTGACCTCCTCCGATTTGAC GluAspLeuLeuGlyCysSerProGlyAspLeuLeuArgPheAsp

451 GATTACAACAGTGACAGCTCCCTGACCCTCCGCGAGTTCTACATG AspTyrAsnSerAspSerSerLeuThrLeuArgGluPheTyrMet

496 GCCTTCCAAGTGGTTCAGCTCAGCCTCGCCCCCGAGGACAGGGTC AlaPheGlnValValGlnLeuSerLeuAlaProGluAspArg¥al

541 AGTGTGACCACAGTGACCGTGGGGCTGAGCACAGTGCTGACCTGC SerValThrThrValThrValGlyLeuSerThrValLeuThrCys 586 GCCGTCCATGGAGACCTGAGGCCACCAATCATCTGGAAGCGCAAC AlaValHisGlyAspLeuArgProProIlelleTrpLysArgAsn

631 GGGCTCACCCTGAACTTCCTGGACTTGGAAGACATCAATGACTTT GlyLeuThrLeuAsnPheLeuAspLeuGluAspIleAsriAspPhe

676 GGAGAGGATGATTCCCTGTACATCACCAAGGTGACCACCATCCAC GlyGluAspAspSerLeuTyrlleThrLysValThrThrlleHis

721 ATGGGCAATTACACCTGCCATGCTTCCGGCCACGAGCAGCTGTTC MetGlyAsnTyrThrCysHisAlaSerGlyHisGluGlnLeuPhe

766 CAGACCCACGTCCTGCAGGTGAATGTGCCGCCAGTCATCCGTGTC GlnThrHisValLeuGlnValAsnValProProVallleArgVal 811 TATCCAGAGAGCCAGGCACAGGAGCCTGGAGTGGCAGCCAGCCTA TyrProGluSerGlnAlaGlnGluProGly¥alAlaAlaSerLeu

856 AGATGCCATGCTGAGGGCATTCCCATGCCCAGAATCACTTGGCTG ArgCysHisAlaGluGlylleProMetProArglleThrTrpLeu

901 AAAAACGGCGTGGATGTCTCAACTCAGATGTCCAAACAGCTCTCC LysAsnGlyValAspValSerThrGlnMetSerLysGlnLeuSer

946 CTTTTAGCCAATGGGAGCGAACTCCACATCAGCAGTGTTCGGTAT LeuLeuAlaAsnGlySerGluLeuHisIleSerSerValArgTyr

991 GAAGACACAGGGGCATACACCTGCATTGCCAAAAATGAAGTGGGT GluAspThrGlyAlaTyrThrCysIleAlaLysAsnGluValGly 1036 GTGGATGAAGATATCTCCTCGCTCTTCATTGAAGACTCAGCTAGA ValAspGluAspIleSerSerLeuPhelleGluAspSerAlaArg

1081 AAGACCCTTGCAAACATCCTGTGGCGAGAGGAAGGTACCAAGCTT LysThrLeuAlaAsnlleLeuTrpArgGluGluGlyThrLysLeu

1126 CATTGTTTTGCGTCATGCCTGTGATCACGTGTGTTTGGTTCTATG HisCysPheAlaSerCysLeu

1171 ATGGGCCGTCTTTCCATGATCTGCCACCAGCTTTCCCACACAAAG 1216 CAGCCCTATGGGAGCAGGAAGTCAATGTCAAATTCAAGTGGCATA 1261 TGCATTGAATCAAATTTAAAATGTACTCCTGTCTTTAATGAGAAA

1306 TTTTTAAATGCAAAGCTTTCATTAAAAGTGGCTTGTAACCTCTGC 1351 TGAAGCAGAACAGTTGGTAAGGGTTCCTGGTCAGATCTGGGCCTT 1396 AAACTTTTTTCCAGTAGCTGACTGGTGTTGGGTTTAGTGTTTTGC 1441 CTATCTTGTGTGGTTTTAAAAAGACAAAACAAGTTGTAGATCTCT

1486 ACTAGATAGTCACTGTACCTTAAATATGCTTTGATTGAGGAAAAC 1531 CCGAGGAAAAAGCTGCCATGATTTCTGCCAATGTATATTTTTAAA 1576 TGTATAGATGTTTAGAAACATATTTATCAAGCAAATCTTTAGTAA 1621 GTTGAGCCATATGAAGTTGCCATTTTTGTGCATCAAAGTGGTCTA 1666 AGATTGACAATTTCATATGGCTGA

Database similarity searches indicate that the protein encoded by clone 4324229 has similarity to a fragment of human limbic system associated membrane protein (LAMP; PCT Publication WO9630052-A1, published 03-OCT-1996). LAMP is a self- binding, antibody-like cell surface adhesion protein involved in formation of connections between adjacent neurons. LAMP protein, and by analogy the clone 4324229 protein, may be important in nerve growth and differentiation, epilepsy, Alzheimer's disease and schizophrenia.

The protein encoded by clone 4324229 is also similar to portions of human Down syndrome-cell adhesion molecule (DS-CAM2), a protein of 1571 residues (PCT Publication W09817795-A1, published 30-APR-1998). DS-CAM2 is a soluble extracellular protein belonging to a novel subclass ofthe Ig superfamily, with highest homology to neural cell adhesion molecules. DS-CAM polypeptides are associated with developmental and neurological processes. DS-CAM polypeptides, and by analogy the clone 4324229 polypeptides, can be used in, e.g. neural prosthetic devices used in entubulation methods of repairing (regenerating) damaged or severed peripheral nerves, and in bioassays to identify agonists and antagonists to said proteins and processes. The clone 4324229 polypeptides can also be used in detection, diagnosis and therapy of developmental and neurological abnormalities such as Down syndrome, mental retardation, holoprosencephaly, agenesis ofthe corpus callosum, or schizencephaly. In a BLASTN similarity search, a 895 bp portion ofthe clone 4324229 nucleotide sequence was found to be 100%) identical to the sequence of human mRNA for KIAA1061 protein (GenBank-ID:AB028984|acc:AB028984, submitted 17-JUN-1999). KIAA1061 originates in brain and its sequence falls within the ORF identified above for clone 4324229. A BLASTP similarity was found to FRAZZLED of Drosophila melanogaster

(ACC:Q94537).

Clone 4324229 proteins include the full length protein encoded by the ORF disclosed herein, as well as any mature protein arising therefrom. Such a mature protein could be formed, for example, as a result ofthe removal of a signal peptide. Clone

4324229 also includes all fragments, analogs, homologs and derivatives of Clone

4324229. Thus the proteins ofthe invention encompass both the precursors and the active forms of Clone 4324229 protein.

MOLl 6 or 4324229-2 Clone 4324229-2 includes a polynucleotide of 4000 bp (SEQ ID NO: 149), shown in Table

AAH. This clone incorporates extensions in both the 5' and 3' directions ofthe nucleotide sequence of clone 4324229 disclosed above. It also is closely related to the nucleotide sequence of clone AC012614-1.0.123 disclosed in the following section. Clone 4324229-2 was originally identified in lymph node. Clone 4324229-2 nucleotide sequence encodes a polypeptide of 842 amino acid residues (SEQ ID NO: 150), shown in Table AAH. This polypeptide is encoded by an open reading frame beginning at nucleotides 408-410, with a termination codon at nucleotides

2934-2936.

Table AAH. Sequence of Clone 4324229-2

1 GGAGAGGGCTGCATTGCTGTTGCTCACTGACCTTCTTTTATGCTGGCCTTTGGTTCAGAATGGCACATCATTCCTCGTTT

8 II TTGGCCCTCCAGCTGAACACCTGTTCTCTGTGGCACTGACTCCTCTTTCCATAGGGACATCATACAACAGTCGCCTTTAT 16 111 CTGAGGTTGTGCAAAGAGGGATGGAGGAGAAAACAATGGAGAATCCCTGGCAGATTTCCCCAGGACGAGAGAAGGATATC 24 ;11 CAATTGCTCATCAGGGAAGGTGCTAGGTCTCCCAGCCAGACGCCCTCAGAGGCCGGTGTCAAGTCTCCCTCACCTCTGTG 3 3221 ATGTGAAGTCAGCTCGTTCATGACCTGGGCAGUCAGAGGGTCAGAGGGGCAGATGGAGCACTCCTGGCCTGATGAAGACT

CATCAAAATGAAACCAGGAGGCTTTTGGCTGCATCTCACACTGCTCGGAGCCTCCCTGCCGGCTGCGCTGGGATGGATGG

MetLysProGlyGlyPheTrp euHisLeuThrLeuLεuGlyAlaSerLeuProAlaAlaLeuGlyTrpMetA

ACCCAGGAACCAGCAGAGGCCCGGATGTGGGTGTGGGGGAGTCACAGGCAGAGGAGCCCAGAAGCTTTGAAGTCACAAGA spProGlyThrSerArgGlyProAspValGlyValGlyGluSerGlnAlaGluGluProArgSerPheGluValThrArg

₆₁ AGAGAAGGGCTTTCCAGCCACAACGAGCTGCTGGCCTCCTGCGGGAAGAAGTTCTGCAGCCGAGGGAGCCGGTGCGTGCT

ArgGluGlyLeuSerSerHisAsnGlu eu euAlaSerCysGly ysLysPheCysSerArgGlySerArgCysValLe

₆₄₁ CAGCAGGAAGACAGGGGAGCCCGAATGCCAGTGCCTGGAGGCATGCAGGCCCAGCTACGTGCCTGTGTGCGGCTCTGATG uSerArgLysThrGlyGluProGluCysGlnCys euGluAlaCysArgProSerTyrValProValCysGlySerAspG

. GGAGGTTTTATGAAAACCACTGTAAGCTCCACCGTGCTGCTTGCCTCCTGGGAAAGAGGATCACCGTCATCCACAGCAAG lyArgPheTyrGluAsnHisCysLysLeuHisArgAlaAlaCysLeuLeuGly ysArglleThrVallleHisSerLys

_{Q 1} GACTGTTTCCTCAAAGGTGACACGTGCACCATGGCCGGCTACGCCCGCTTGAAGAATGTCCTTCTGGCACTCCAGACCCG

AspCysPheLeuLysGlyAspThrCysThrMetAlaGlyTyrAlaArg euLysAsnValLeu euAlaLeuGlnThrAr

₈₁ TCTGCAGCCACTCCAAGAAGGAGACAGCAGACAAGACCCTGCCTCCCAGAAGCGCCTCCTGGTGGAATCTCTGTTCAGGG gLeuGlnProLeuGlnGluGlyAspSerArgGlnAspProAlaSerGlnLysArg euLeuValGluSerLeuPheArgA

961 . ACTTAGATGCAGATGGCAATGGCCACCTCAGCAGCTCCGAACTGGCTCAGCATGTGCTGAAGAAGCAGGACCTGGATGAA spLeuAspAlaAspGlyAsnGlyHisLeuSerSerSerGluLeuAlaGlnHisVal euLysLysGlnAsp euAspGlu 1 ₀0₄4₁1 GACTTACTTGGTTGCTCACCAGGTGACCTCCTCCGATTTGACGATTACAACAGTGACAGCTCCCTGACCCTCCGCGAGTT

Asp euLeuGlyCysSerProGlyAspLeuLeuArgPheAspAspTyrAsnSerAspSerSerLeuThrLeuArgGluPh

1121 ^CTACATGG TTCCAAGTGGTTCAGCTCAGCCTCGCCCCCGAGGACAGGGTCAGTGTGACCACAGTGACCGTGGGGCTGA eTyrMetAlaPheGlnValValGlnLeuSerLeuAlaProGluAspArgValSerValThrThrValThrValGlyLeuS

₁₂₀₁ GCACAGTGCTGACCTGCGCCGTCCATGGAGACCTGAGGCCACCAATCATCTGGAAGCGCAACGGGCTCACCCTGAACTTC erThrValLeuThrCysAlaValHisGlyAspLeuArgProProIlelleTrpLysArgAsnGlyLeuThrLeuAsnPhe

_12gl CTGGACTTGGAAGACATCAATGACTTTGGAGAGGATGATTCCCTGTACATCACCAAGGTGACCACCATCCACATGGGCAA

LeuAsp euGluAspIleAsnAspPheGlyGluAspAspSerLeuTyrlleThrLysValThrThrlleHisMetGlyAs

1361 ^{TTACA T|}3CCATGCTTCCGGCCACGAGCAGCTGTTCCAGACCCACGTCCTGCAGGTGAATGTGCCGCCAGTCATCCGTG riTyrThrCysHisAlaSerGlyHisGluGln euPheGlnThrHisVal euGlnValAsnValProProVallleArgV

_144χ TCTATCCAGAGAGCCAGGCACAGGAGCCTGGAGTGGCAGCCAGCCTAAGATGCCATGCTGAGGGCATTCCCATGCCCAGA alTyrProGluSerGlnAlaGlnGluProGlyValAlaAlaSerLeuArgCysHisAlaGluGlylleProMetProArg _n _,_ ATCACTTGGCTGAAAAACGGCGTGGATGTCTCAACTCAGATGTCCAAACAGCTCTCCCTTTTAGCCAATGGGAGCGAACT

IleThrTrp eu ysAsnGlyValAspValSerThrGlnMetSer ysGlnLeuSer eu euAlaAsnGlySerGluLe 1601 CCACATCAGCAGTGTTCGGTATGAAGACACAGGGGCATACACCTGCATTGCCAAAAATGAAGTGGGTGTGGATGAAGATA uHisIleSerSerValArgTyrGluAspThrGlyAlaTyrThrCysIleAlaLysAsnGluValGlyValAspGluAspI 1681 TCTCCTCGCTCTTCATTGAAGACTCAGCTAGAAAGACCCTTGCAAACATCCTGTGGCGAGAGGAAGGCCTCAGCGTGGGA leSerSerLeuPhelleGluAspSerAlaArg ysThrLeuAlaAsnlleLeuTrpArgGluGluGlyLeuSerValGly 1761 AACATGTTCTATGTCTTCTCCGACGACGGTATCATCGTCATCCATCCTGTGGACTGTGAGATCCAGAGGCACCTCAAACC AsnMetPheTyrValPheSerAspAspGlyllelleVallleHisProValAspCysGluIleGlnArgHisLeuLysPr 1841 CACGGAAAAGATTTTCATGAGCTATGAAGAAATCTGTCCTCAAAGAGAAAAAAATGCAACCCAGCCCTGCCAGTGGGTAT oThrGlu ysIlePheMetSerTyrGl GluIleCysProGlnArgGlu ysAsnAlaThrGlnProCysGlnTrpValS 1921 CTGCAGTCAATGTCCGGAACCGGTACATCTATGTGGCCCAGCCAGCACTGAGCAGAGTCCTTGTGGTCGACATCCAAGCC erAlaValAsnValArgAsnArgTyrlleTyrValAlaGlnProAlaLeuSerArgVal euValValAspIleGlnAla 2001 CAGAAAGTCCTACAGTCCATAGGTGTGGACCCTCTGCCGGCTAAGCTGTCCTATGACAAGTCACATGACCAAGTGTGGGT GlnLysValLeuGlnSerlleGlyValAspProLeuProAlaLysLeuSerTyrAsp ysSerHisAspGlnValTrpVa 2081 CCTGAGCTGGGGGGACGTGCACAAGTCCCGACCAAGTCTCCAGGTGATCACAGAAGCCAGCACCGGCCAGAGCCAGCACC l euSerTrpGlyAspValHisLysSerArgProSer euGlnVallleThrGluAlaSerThrGlyGlnSerGlnHisL 2161 TCATCCGCACACCCTTTGCAGGAGTGGATGATTTCTTCATTCCCCCAACAAACCTCATCATCAACCACATCAGGTTTGGC eulleArgThrProPheAlaGlyValAspAspPhePhelleProProThrAsnLeuIlelleAsnHisIleArgPheGly 2241 TTCATCTTCAACAAGTCTGATCCTGCAGTCCACAAGGTGGACCTGGAAACAATGATGCCCCTCAAGACCATCGGCCTGCA PhellePheAsn ysSerAspProAlaValHisLysValAspLeuGluThrMetMetPro euLysT rlleGlyLeuHi 2321 CCACCATGGCTGCGTGCCCCAGGCCATGGCACACACCCACCTGGGCGGCTACTTCTTCATCCAGTGCCGACAGGACAGCC sHisHαsGlyCysValProGlnAlaMetAlaHisThrHis euGlyGlyTyrPhePhelleGlnCysArgGlnAspSerP 2401 CCGCCTCTGCTGCCCGACAGCTGCTCGTTGACAGTGTCACAGACTCTGTGCTTGGCCCCAATGGTGATGTAACAGGCACC roAlaSerAlaAlaArgGln euLeuValAspSerValThrAspSerValLeuGlyProAsnGlyAspValThrGlyThr 2481 CCACACACATCCCCCGACGGGCGCTTCATAGTCAGTGCTGCAGCTGACAGCCCCTGGCTGCACGTGCAGGAGATCACAGT ProHisThrSerProAspGlyArgPhelleValSerAlaAlaAlaAspSerProTrpLeuHisValGlnGluIleThrVa 2561 GCGGGGCGAGATCCAGACCCTGTATGACCTGCAAATAAACTCGGGCATCTCAGACTTGGCCTTCCAGCGCTCCTTCACTG lArgGlyGluIleGlnThr euTyrAspLeuGlnlleAsnSerGlylleSerAspLeuAlaPheGlnArgSerPheThrG 2641 AAAGCAATCAATACAACATCTACGCGGCTCTGCACACGGAGCCGGACCTGCTGTTCCTGGAGCTGTCCACGGGGAAGGTG luSerAsnGlnTyrAsnlleTyrAlaAla euHisThrGluProAspLeuLeuPhe euGlu euSerThrGlyLysVal 2721 GGCATGCTGAAGAACTTAAAGGAGCCACCCGCAGGGCCAGCTCAGCCCTGGGGGGGTACCCACAGAATCATGAGGGACAG GlyMetLeuLysAsnLeu ysGluProProAlaGlyProAlaGlnProTrpGlyGlyThrHisArglleMetArgAspSe 2801 TGGGCTGTTTGGACAGTACCTCCTCACACCAGCCCGAGAGTCACTGTTCCTCATCAATGGGAGACAAAACACGCTGCGGT rGly euPheGlyGlnTyrLeuLeuThrProAlaArgGluSerLeuPheLeuIleAsnGlyArgGlnAsnThrLeuArgC 2881 GTGAGGTGTCAGGTATAAAGGGGGGGACCACAGTGGTGTGGGTGGGTGAGGTATGAAGGGCCCAGAGCAGAGCCCTGGGC ysGluValSerGlylle ysGlyGlyT rThrValValTrpValGlyGluVal 2961 CAAGGAACACCCCCTAGTCCTGACACTGCAGCCTCAAGCAGGTACGCTGTACATTTTTACAGACAAAAGCAAAAACCTGT 3041 ACTCGCTTTGTGGTTCAACACTGGTCTCCTTGCAAGTTTCCTAGTATAAGGTATGCGCTGCTACCAAGATTGGGGTTTTT 3121 TCGTTAGGAAGTATGATTTATGCCTTGAGCTACGATGAGAACATATGCTGCTGTGTAAAGGGATCATTTCTGTGCCAAGC 3201 TGCACACCGAGTGACCTGGGGACATCATGGAACCAAGGGATCCTGCTCTCCAAGCAGACACCTCTGTCAGTTGCCTTCAC 3281 ATAGTCATTGTCCCTTACTGCCAGACCCAGCCAGACTTTGCCCTGACGGAGTGGCCCGGAAGCAGAGGCCGACCAGGAGC 3361 AGGGGCCTCCCTCCCGAACTGAAAGCCCATCCGTCCTCGCGTGGGACCGCATCTTCTCCCTCGCAGCTGCTTCTTGCTTT 3441 TCTTTCCATTTGACTTGCTGTAAGCCTGAGGGAGAGCCAACAAGACTTACTGCATCTTGGGGGATGGGGAAATCACTCAC 3521 TTTATTTTGGAAATTTTTGATTAAAAAAAAATTTTATAATCTCAAATGCTAGTAAGCAGAAAGATGCTCTCCGAGGTCCA 3601 ACTATATCCTTCCCTGCCTTAGGCCGAGTCTCGGGGGTGGTCACAACCCCACATCCCACAGCCAGAAAGAACAATGGTCA 3681 TCTGAGAATACTGGCCCTGTCGACTATTGCCACCCTGCTTCTCCAAGAGCAGACCAGGCCACCTCATCCGTAAGGACTCG 3761 GTTCTGTGTTGGGACCCCAAAAAACCAGAACAAGTTCTGTGTGCCTCCTTTCAGCACAGAAGGGAGACATCTCATTAGTC 3841 AGGTCTGGTACCCCAGATTCAGGGCAGACTGGGCTTGCCTGGCAAGGTATGGGTGGCCTCCAGGCTCAATGCAGAAACCC

3921 CAAGGACACGAGTGGGGCCAGGTGAGTTCCTGAAGCTATACCTTTTCAAAACAGATTTTGTTTTCCTACCTGTGGCCCAT 4001 CCACTCCTCTCTGGTACCCCATCCCCGCATCAGCACTGCAGAGAGAACACATTTCGGCGAGGGTTTTCTTACCCACATTC 4081 CCCAATCAATACACACACACTGCAGAACCCAGAACAGAAGGCCACAGGCTGGCACTACTGCATTCTCCTTATGTGTCTCA 4161 GGCTGTGGTGACTCTCACATGGGCATCGAAGAAGTACAACCCACATAGCCCTCTGGAGACCGCCTAGATCAGAGACTCAG 4241 CAAAAACAGGCTCGCCTTCCCTCTCCCACATATGAGTGGAACTTACATGTGTCCTGGTTTGAATGATCATTTTGCAAGCC 4321 ACACGGGTTGGGAGAGGTGGTCTCACCACAGACGTCTTTGCTAATTTGGCCACCTTCACCTACTGACATGACCAGGATTT 4401 TCCTTTGCCATTAAGGAATGAACTCTTTCAAGGAGAGGAAACCCTAGACTCTGTGTCACTCTCAACACACACAGCTCCTT 4481 TCACTCCTGCCTGACTGCCAAGCCACCTGCATCCCCCGCCCCAGATCTCATGAGATCAATCACTTGTATGTCTCACGCAA 4561 CTTGGTCCACCAAACGCCTGTCCCCTGTAACTCCTAGGGGTGCGCCTAGACAGGTACGTCTGTTTTTTATTTTAAAAGAT 4641 ATGCTATGTAGATATAAGTTGAGGAAGCTCACCTCAAAAGCCTAGAATGCAGTTTCACAGTAGCTGGGATGCATGGATGA 4721 CCCATCTCACCCCTTTTTTTTTCCTGCCTCAATATCTTGATATGTTATGTTTACTCCCAATCTCCCATTTTTACCACTAA

4801 AATTCTCCAACTTTCATAAACTTTTTTTTGGAAAAATTTCCATTGTATCAGCCCCTGACAGAAAAAGGATCTCTGAGCCT 4881 AAAGGAGGAAAAGTCCCACCAACTACCAGACCAGAACACGAGCCCCTCTGGGCAGCAGGATTCCTAAGTCAAAGACCAGT 4961 TTGACCCAAACTGGCCTTTTAAAATAATCAGGAGTGACAGAGTCAACTTCTGCAGCACCTGCTTCTCCCCCACTGTCCCT 5041 TCCATCTTGGAATGTGTCTAAAAAAGCATAGCTGCCCTTTGCTGTCCTCAGAGTGCATTTCCTGGAGACGGCAGGCTTAG 5121 GTCTCACTGACAGCATGCCAGACACAACTGAATCGAAGCAGGCCTGAAGCCTAGGTCAGGGTTTCAGGAGTCCAGCCCCA 5201 GGAGGCAAAGTCACCAATGCAGGGAGGTAAATGCCTTTTGGCAGGAAAACCAATAGAGTTGGTTGGGTGGGGAGTCAGGG

5281 GTGGGAGGAGAAGGAGGAAGAGGAGGAAGGCCAGACTGGCCTGCCCTTTCTCCCATACTTCACCCCAGCAGAGGTTCATG

5361 GGACACAGTTGGAAAGCCACTGGGAGGAAATGCCTCACTACAGGGGGGCCTCCTGTAGCAAGCCCAGCCGGTAATCCTCC 5441 TAATGAACCCACAAGGTCAATTCACAACTGATATCTTAGCTATTAAAGAAGTACTGACTTTACCAAAAGAATCATCAAGA 5521 AAGCTATTTATATAAACCCCCTCAGTCATTTTGAAATAAAATTAATTTTACAA

BLASTX analysis indicates that a portion ofthe C-terminus of Clone 4324229-2 protein is identical to KIAA1061. See DNA Res. 6:197-205(1999); GenBank- ID:AB028984|acc:AB028984. It is similar to cell adhesion molecules and follistatin-like proteins.

Clone 4324229-2 proteins include the full length protein encoded by the ORF disclosed herein, as well as any mature protein arising therefrom. Such a mature protein could be formed, for example, as a result ofthe removal of a signal peptide. Clone 4324229-2 also includes all fragments, analogs, homologs and derivatives of Clone 4324229-2. Thus the proteins ofthe invention encompass both the precursors and the active forms of a LAMP-like and DS-CAM-like Clone 4324229-2 protein. MOL17 or AC012614J.0.123 AC012614 .0.123 includes a full-length clone of 5502 nucleotides (SEQ ID NO:

151) and the entire coding sequence of a predicted 815 amino acid protein (SEQ ID NO: 152), shown in Table AAI. The predicted ORF spans from nucleotides 420 to 2865. This sequence is expressed in glioma, osteoblast, other cancer cells, lung carcinoma, and small intestine. Table AAI . Sequence of Clone AC012614_1 . 0 . 123

Frame : 3 - Nucleotide 420 to 2864 Printed 80 characters to a line . i

CAATTTCACACAGGAAACAGCTATGCCATGATTACGCAAGTTGGTACCGAGCTCGGATCCACTAGTAACGGCCGCCAGTG 81

TGCTGGAATTCGGCTTACTCACTATAGGGCTCGAGCGGCTGCCCGGGCAGGTCATTAATTCCATTTCTTTTTAGAGTATC 161

ACAGCTTTCTCCTTCACTGACCACCCTTTGCTTCCTGTCAGAAAGCCCTGGACAGAACTCTCTGTGGGATTCTGCCCATG 241

TTTCTGAGATATCGCCTCAATTGTCCTGGCTGGGCTGTCGGGTCTGCCCGTTTTACAGATGGGCAAACTGGAGTGGGAAG

³²¹ TATCCGGGTGGCTTCCTCAGGCCTGCAGCTGGTGGAGCAGCTACTGAAACAATCAGGAGCCCAGAAGCTTTGAAGTCACA

401

AGAAGAGAAGACTCCCAGAATGCAGTGTGATGTTGGTGATGGACGCCTGTTTCGCCTTTCACTTAAACGTGCCCTTTCCA

MetGlnCysAspValGlyAspGlyArgLeuPheArgLeuSer euLysArgAlaLeuSerS

481 GCTGCCCTGACCTCTTTGGGCTTTCCAGCCGCAACGAGCTGCTGGCCTCCTGCGGGAAGAAGTTCTGCAGCCGAGGGAGC erCysProAsp euPheGlyLeuSerSerArgAsnGluLeuLeuAlaSerCysGlyLysLysPheCysSerArgGlySer

561

CGGTGCGTGCTCAGCAGGAAGACAGGGGAGCCCGAATGCCAGTGCCTGGAGGCATGCAGGCCCAGCTACGTGCCTGTGTG ArgCysValLeuSerArgLysThrGlyGluProGluCysGlnCys euGluAlaCysArgProSerTyrValProValCy 641

CGGCTCTGATGGGAGGTTTTATGAAAACCACTGTAAGCTCCACCGTGCTGCTTGCCTCCTGGGAAAGAGGATCACCGTCA sGlySerAspGlyArgPheTyrGluAsnHisCys ysLeuHisArgAlaAlaCys euLeuGlyLysArglleThrVall 721

TCCACAGCAAGGACTGTTTCCTCAAAGGTGACACGTGCACCATGGCCGGCTACGCCCGCTTGAAGAATGTCCTTCTGGCA leHisSerLysAspCysPheLeu ysGlyAspThrCysThrMetAlaGlyTyrAlaArgLeu ysAsnValLeu euAla 801

CTCCAGACCCGTCTGCAGCCACTCCAAGAAGGAGACAGCAGACAAGACCCTGCCTCCCAGAAGCGCCTCCTGGTGGAATC

LeuGlnThrArgLeuGlnPro euGlnGluGlyAspSerArgGlnAspProAlaSerGlnLysArg eu euValGluSe

881 TCTGTTCAGGGACTTAGATGCAGATGGCAATGGCCACCTCAGCAGCTCCGAACTGGCTCAGCATGTGCTGAAGAAGCAGG r euPheArgAsp euAspAlaAspGlyAsnGlyHisLeuSerSerSerGluLeuAlaGlnHisValLeu ysLysGlnA

961

ACCTGGATGAAGACTTACTTGGTTGCTCACCAGGTGACCTCCTCCGATTTGACGATTACAACAGTGACAGCTCCCTGACC spLeuAspGluAspLeu euGlyCysSerProGlyAsp euLeuArgPheAspAspTyrAsnSerAspSerSer euThr 1041

CTCCGCGAGTTCTACATGGCCTTCCAAGTGGTTCAGCTCAGCCTCGCCCCCGAGGACAGGGTCAGTGTGACCACAGTGAC LeuArgGluPheTyrMetAlaPheGlnValValGlnLeuSerLeuAlaProGluAspArgValSerValThrThrValTh 1121 CGTGGGGCTGAGCACAGTGCTGACCTGCGCCGTCCATGGAGACCTGAGGCCACCAATCATCTGGAAGCGCAACGGGCTCA rValGlyLeuSerThrValLeuThrCysAlaValHisGlyAsp euArgProProIlelleTrpLysArgAsnGly euT

1201

CCCTGAACTTCCTGGACTTGGAAGACATCAATGACTTTGGAGAGGATGATTCCCTGTACATCACCAAGGTGACCACCATC hr euAsnPhe euAspLeuGluAspIleAsnAspPheGlyGluAspAspSerLeuTyrlleTh LysValThrThrlle

1281

CACATGGGCAATTACACCTGCCATGCTTCCGGCCACGAGCAGCTGTTCCAGACCCACGTCCTGCAGGTGAATGTGCCGCC HisMetGlyAsnTyrThrCysHisAlaSerGlyHisGluGlnLeuPheGlnThrHisValLeuGlnValAsnValProPr

1361 AGTCATCCGTGTCTATCCAGAGAGCCAGGCACAGGAGCCTGGAGTGGCAGCCAGCCTAAGATGCCATGCTGAGGGCATTC oVallleArgValTyrProGluSerGlnAlaGlnGluProGlyValAlaAlaSerLeuArgCysHisAlaGluGlylleP

1441

CCATGCCCAGAATCACTTGGCTGAAAAACGGCGTGGATGTCTCAACTCAGATGTCCAAACAGCTCTCCCTTTTAGCCAAT roMetProArglleThrTrp eu ysAsnGlyValAspValSerThrGlnMetSerLysGlnLeuSerLeuLeuAlaAsn 1521

GGGAGCGAACTCCACATCAGCAGTGTTCGGTATGAAGACACAGGGGCATACACCTGCATTGCCAAAAATGAAGTGGGTGT GlySerGlu euHisIleSerSerValArgTyrGluAspThrGlyAlaTyrThrCysIleAlaLysAsnGluValGlyVa

1601

GGATGAAGATATCTCCTCGCTCTTCATTGAAGACTCAGCTAGAAAGACCCTTGCAAACATCCTGTGGCGAGAGGAAGGCC lAspGluAspIleSerSerLeuPhelleGluAspSerAlaArgLysThrLeuAlaAsnlleLeuTrpArgGluGluGlyL

1681

TCAGCGTGGGAAACATGTTCTATGTCTTCTCCGACGACGGTATCATCGTCATCCATCCTGTGGACTGTGAGATCCAGAGG euSerValGlyAsn etPheTyrValPheSerAspAspGlyllelleVallleHisProValAspCysGluIleGlnArg

1761 CACCTCAAACCCACGGAAAAGATTTTCATGAGCTATGAAGAAATCTGTCCTCAAAGAGAAAAAAATGCAACCCAGCCCTG HisLeuLysProThrGlu ysIlePheMetSerTyrGluGluIleCysProGlnArgGluLysAsnAlaThrGlnProCy

1841

CCAGTGGGTATCTGCAGTCAATGTCCGGAACCGGTACATCTATGTGGCCCAGCCAGCACTGAGCAGAGTCCTTGTGGTCG sGlnTrpValSerAlaValAsnValArgAsnArgTyrlleTyrValAlaGlnProAla euSerArgValLeuValValA 1921

ACATCCAAGCCCAGAAAGTCCTACAGTCCATAGGTGTGGACCCTCTGCCGGCTAAGCTGTCCTATGACAAGTCACATGAC spIleGlnAlaGlnLysValLeuGlnSerlleGlyValAspProLeuProAla ysLeuSerTyrAspLysSerHisAsp

2001

CAAGTGTGGGTCCTGAGCTGGGGGGACGTGCACAAGTCCCGACCAAGTCTCCAGGTGATCACAGAAGCCAGCACCGGCCA GlnValTrpVal euSerTrpGlyAspValHis ysSerArgProSer euGlnVallleThrGluAlaSerThrGlyGl

2081

GAGCCAGCACCTCATCCGCACACCCTTTGCAGGAGTGGATGATTTCTTCATTCCCCCAACAAACCTCATCATCAACCACA nSerGlnHisLeuIleArgThrProPheAlaGlyValAspAspPhePhelleProProThrAsn euIlelleAsnHisI

2161 TCAGGTTTGGCTTCATCTTCAACAAGTCTGATCCTGCAGTCCACAAGGTGGACCTGGAAACAATGATGCCCCTCAAGACC leArgPheGlyPhellePheAsnLysSerAspProAlaValHisLysValAspLeuGluThrMetMetPro euLysThr

2241

ATCGGCCTGCACCACCATGGCTGCGTGCCCCAGGCCATGGCACACACCCACCTGGGCGGCTACTTCTTCATCCAGTGCCG IleGlyLeuHisHisHisGlyCysValProGlnAlaMetAlaHisThrHisLeuGlyGlyTyrPhePhelleGlnCysAr

2321

ACAGGACAGCCCCGCCTCTGCTGCCCGACAGCTGCTCGTTGACAGTGTCACAGACTCTGTGCTTGGCCCCAATGGTGATG gGlnAspSerProAlaSerAlaAlaArgGln euLeuValAspSerValThrAspSerValLeuGlyProAsnGlyAspV

2401

TAACAGGCACCCCACACACATCCCCCGACGGGCGCTTCATAGTCAGTGCTGCAGCTGACAGCCCCTGGCTGCACGTGCAG alThrGlyThrProHisThrSerProAspGlyArgPhelleValSerAlaAlaAlaAspSerProTrpLeuHisValGln

2481

GAGATCACAGTGCGGGGCGAGATCCAGACCCTGTATGACCTGCAAATAAACTCGGGCATCTCAGACTTGGCCTTCCAGCG GluIleThrValArgGlyGluIleGlnThr euTyrAsp euGlnlleAsnSerGlylleSerAspLeuAlaPheGlnAr

2561 CTCCTTCACTGAAAGCAATCAATACAACATCTACGCGGCTCTGCACACGGAGCCGGACCTGCTGTTCCTGGAGCTGTCCA gSerPheThrGluSerAsnGlnTyrAsnlleTyrAlaAlaLeuHisThrGluProAspLeu euPheLeuGluLeuSerT

2641

CGGGGAAGGTGGGCATGCTGAAGAACTTAAAGGAGCCACCCGCAGGGCCAGCTCAGCCCTGGGGGGGTACCCACAGAATC hrGlyLysValGlyMetLeu ysAsnLeuLysGluProProAlaGlyProAlaGlnProTrpGlyGlyThrHisArglle

2721

ATGAGGGACAGTGGGCTGTTTGGACAGTACCTCCTCACACCAGCCCGAGAGTCACTGTTCCTCATCAATGGGAGACAAAA MetArgAspSerGlyLeuPheGlyGlnTyr eu euThrProAlaArgGluSerLeuPhe euIleAsnGlyArgGlnAs

2801

CACGCTGCGGTGTGAGGTGTCAGGTATAAAGGGGGGGACCACAGTGGTGTGGGTGGGTGAGGTATGAAGGGCCCAGAGCA nThrLeuArgCysGluValSerGlylleLysGlyGlyThrThrValValTrpValGlyGluVal

2881

GAGCCCTGGGCCAAGGAACACCCCCTAGTCCTGACACTGCAGCCTCAAGCAGGTACGCTGTACATTTTTACAGACAAAAG

2961

CAAAAACCTGTACTCGCTTTGTGGTTCAACACTGGTCTCCTTGCAAGTTTCCTAGTATAAGGTATGCGCTGCTACCAAGA 3041

TTGGGGTTTTTTCGTTAGGAAGTATGATTTATGCCTTGAGCTACGATGAGAACATATGCTGCTGTGTAAAGGGATCATTT

3121

CTGTGCCAAGCTGCACACCGAGTGACCTGGGGACATCATGGAACCAAGGGATCCTGCTCTCCAAGCAGACACCTCTGTCA

3201 GTTGCCTTCACATAGTCATTGTCCCTTACTGCCAGACCCAGCCAGACTTTGCCCTGACGGAGTGGCCCGGAAGCAGAGGC

3281 CGACCAGGAGCAGGGGCCTCCCTCCCGAACTGAAAGCCCATCCGTCCTCGCGTGGGACCGCATCTTCTCCCTCGCAGCTG 3361

CTTCTTGCTTTTCTTTCCATTTGACTTGCTGTAAGCCTGAGGGAGAGCCAACAAGACTTACTGCATCTTGGGGGATGGGG 3441

AAATCACTCACTTTATTTTGGAAATTTTTGATTAAAAAAAAATTTTATAATCTCAAATGCTAGTAAGCAGAAAGATGCTC 3521

TCCGAGGTCCAACTATATCCTTCCCTGCCTTAGGCCGAGTCTCGGGGGTGGTCACAACCCCACATCCCACAGCCAGAAAG 3601

AACAATGGTCATCTGAGAATACTGGCCCTGTCGACTATTGCCACCCTGCTTCTCCAAGAGCAGACCAGGCCACCTCATCC 3681

GTAAGGACTCGGTTCTGTGTTGGGACCCCAAAAAACCAGAACAAGTTCTGTGTGCCTCCTTTCAGCACAGAAGGGAGACA 3761

TCTCATTAGTCAGGTCTGGTACCCCAGATTCAGGGCAGACTGGGCTTGCCTGGCAAGGTATGGGTGGCCTCCAGGCTCAA 3841 TGCAGAAACCCCAAGGACACGAGTGGGGCCAGGTGAGTTCCTGAAGCTATACCTTTTCAAAACAGATTTTGTTTTCCTAC 3921

CTGTGGCCCATCCACTCCTCTCTGGTACCCCATCCCCGCATCAGCACTGCAGAGAGAACACATTTCGGCGAGGGTTTTCT 4001

TACCCACATXCCCCAATCAATACACACACACTGCAGAACCCAGAACAGAAGGCCACAGGCTGGCACTACTGCATTCTCCT 4081

TATGTGTCTCAGGCTGTGGTGACTCTCACATGGGCATCGAAGAAGTACAACCCACATAGCCCTCTGGAGACCGCCTAGAT 4161

CAGAGACTCAGCAAAAACAGGCTCGCCTTCCCTCTCCCACATATGAGTGGAACTTACATGTGTCCTGGTTTGAATGATCA 4241 TTTTGCAAGCCACACGGGTTGGGAGAGGTGGTCTCACCACAGACGTCTTTGCTAATTTGGCCACCTTCACCTACTGACAT 4321

GACCAGGATTTTCCTTTGCCATTAAGGAATGAACTCTTTCAAGGAGAGGAAACCCTAGACTCTGTGTCACTCTCAACACA 4401

CACAGCTCCTTTCACTCCTGCCTGACTGCCAAGCCACCTGCATCCCCCGCCCCAGATCTCATGAGATCAATCACTTGTAT 4481

GTCTCACGCAACTTGGTCCACCAAACGCCTGTCCCCTGTAACTCCTAGGGGTGCGCCTAGACAGGTACGTCTGTTTTTTA 4561

TTTTAAAAGATATGCTATGTAGATATAAGTTGAGGAAGCTCACCTCAAAAGCCTAGAATGCAGTTTCACAGTAGCTGGGA 4641

TGCATGGATGACCCATCTCACCCCTTTTTTTTTCCTGCCTCAATATCTTGATATGTTATGTTTACTCCCAATCTCCCATT 4721

TTTACCACTAAAATTCTCCAACTTTCATAAACTTTTTTTTGGAAAAATTTCCATTGTATCAGCCCCTGACAGAAAAAGGA 4801

TCTCTGAGCCTAAAGGAGGAAAAGTCCCACCAACTACCAGACCAGAACACGAGCCCCTCTGGGCAGCAGGATTCCTAAGT 4881

CAAAGACCAGTTTGACCCAAACTGGCCTTTTAAAATAATCAGGAGTGACAGAGTCAACTTCTGCAGCACCTGCTTCTCCC 4961

CCACTGTCCCTTCCATCTTGGAATGTGTCTAAAAAAGCATAGCTGCCCTTTGCTGTCCTCAGAGTGCATTTCCTGGAGAC 5041

GGCAGGCTTAGGTCTCACTGACAGCATGCCAGACACAACTGAATCGAAGCAGGCCTGAAGCCTAGGTCAGGGTTTCAGGA 5121

GTCCAGCCCCAGGAGGCAAAGTCACCAATGCAGGGAGGTAAATGCCTTTTGGCAGGAAAACCAATAGAGTTGGTTGGGTG 5201

GGGAGTCAGGGGTGGGAGGAGAAGGAGGAAGAGGAGGAAGGCCAGACTGGCCTGCCCTTTCTCCCATACTTCACCCCAGC 5281

AGACGTTCATGGGACACAGTTGGAAAGCCACTGGGAGGAAATGCCTCACTACAGGGGGGCCTCCTGTAGCAAGCCCAGCC 5361

GGTAATCCTCCTAATGAACCCACAAGGTCAATTCACAACTGATATCTTAGCTATTAAAGAAGTACTGACTTTACCAAAAG 5441 AATCATCAAGAAAGCTATTTATATAAACCCCCTCAGTCATTTTGAAATAAAATTAATTTTAC

AC012614_1.0.123 maps to the Unigene entry 123420, which is expressed in brain, breast, kidney, pancreas, and pooled tissue. This entry further maps to the Chromosome 5 marker stSG63086 (also known as RH104076) (GM99-GB4 Map information); Position: 510.63 (cR3000); Lod score:0.71; Reference Interval: D5S471- D5S393 (129.6-140.8 cM). By integrating the marker information with the MIM gene map, it is believed clone ACO 12614_1.0.123 maps to 5q21 -5q31.

AC012614_1.0.123 was searched against other databases using SignalPep and PSort search protocols. The protein is most likely located in the mitochondrial matrix space (certainty=0.4718) and seems to have no known N-terminal signal sequence. The predicted molecular weight is 90346.9 daltons.

The predicted AC012614_1.0.123 amino acid sequence was searched in the publicly available GenBank database using BLASTP. The 815 residue AC012614_1.0.123 protein shows 100% identity (693 of 693 amino acids) with the 693 aa human KIAA 1061 protein fragment (ACC:BAA83013). AC012614_1.0.123 protein is similar to cell adhesion molecules; to murine, rat, Xenopus and human follistatin-related protein precursor (TGF-beta-inducible protein TSC-36, a protein of about 300 residues in the various species); and to short segments of Drosophila roundabout and fi-azzled. These genes are involved in neuronal development and reproductive physiology. By analogy, AC012614_1.0.123 proteins and polypeptides may also be involved in neuronal development and reproductive physiology.

Frazzled encodes & Drosophila member ofthe DCC immunoglobulin subfamily and is required for CNS and motor axon guidance. Cell 87: 197-204(1996). Characterization of a rat C6 glioma-secreted follistatin-related protein (FRP) and cloning and sequence ofthe human homologue is described in Eur. J. Biochem. 225:937- 946(1994). This protein may modulate the action of some growth factors on cell proliferation and differentiation. FRP binds heparin. The follistatin-related protein is a secreted protein and has one follistatin-like domain. The cloning and early dorsal axial expression of Flik, a chick follistatin-related gene and evidence for involvement in dorsalization/neural induction is described in Dev. Biol. 178:327-342(1996). Roundabout controls axon crossing ofthe CNS midline and defines a novel subfamily of evolutionarily conserved guidance receptors, as shown in Cell 92:205-21.5(1998). cDNA cloning and structural analysis ofthe human limbic-system- associated membrane protein (LAMP) is described in Gene 170:189-195(1996). LAMP, a protein ofthe OBCAM family that contains three immunoglobulin-like C2-type domains, mediates selective neuronal growth and axon targeting. LAMP contributes to the guidance of developing axons and remodeling of mature circuits in the limbic system. This protein is essential for normal growth ofthe hippocampal mossy fiber projection. LAMP is attached to the membrane by a GPI-Anchor. It is expressed on limbic neurons and fiber tracts as well as in single layers of the superior colliculus, spinal chord and cerebellum. Characterization ofthe human full- length PTK7 cDNA encoding a receptor protein tyrosine kinase-like molecule closely related to chick KLG is disclosed in J. Biochem. 1 19:235-239(1996). Based upon homology, AC012614_1.0.012 proteins and each homologous protein or peptide may share at least some activity.

The region to which AC012614_1.0.123 maps is listed in the National Center for Biotechnology Information website for the Online Mendelian Inheritance in Man (OMIM™) gene map (URL: "www.ncbi.nlm.nih.gov/Omim/") to be associated with susceptibility to the following diseases (where available, OMIM™ identifying numbers are underlined): allergy and asthma; hemangioma; capillary infantile Schistosoma mansoni infection; susceptibility/resistance to Spinocerebellar ataxia; bronchial asthma; Plasmodium falciparum parasitemia; intensity of Corneal dystrophy, Groenouw type I (OMIM™ 121900); corneal dystrophy, lattice type I (OMIM™ 122200); Reis-Bucklers corneal dystrophy; corneal dystrophy, Avellino type eosinophilia, familial myelodysplastic syndrome; myelogenous leukemia, acute Cutis laxa, recessive, type I; deafness, autosomal dominant non-syndromic sensorineural; 1 contractural arachnodactyly; congenital neonatal alloimmune thrombocytopenia; glycoprotein la deficiency male infertility; Charcot-Marie- Tooth neuropathy, demyelinating Gardner syndrome; adenomatous polyposis coli; colorectal cancer; desmoid disease, hereditary (OMIM™ 135290); Turcot syndrome (OMIM™ 276300); and adenomatous polyposis coli, attenuated. By analogy, clone AC012614_1.0.123 is implicated in at least all ofthe above mentioned diseases and may have therapeutic uses for these diseases.

Clone AC012614_1.0.123 has similarity to cell adhesion molecules, follistatin, roundabout and frazzled. These genes are involved in neuronal development and reproductive physiology. Therefore Clone AC012614_1.0.123 is also implicated in disorders such as or therapeutic uses for nerve trauma, neurodegenerative disorders, epilepsy, mental health conditions, tissue regeneration in vivo and in vitro, and female reproductive system disorders and pregnancy. Clone AC012614_1.0.123 proteins include the full length protein encoded by the

ORF disclosed herein, as well as any mature protein arising therefrom. Such a mature protein could be formed, for example, as a result ofthe removal of a signal peptide. Clone AC012614_1.0.123 also includes all fragments, analogs, homologs and derivatives of Clone AC012614_1.0.123. Thus the invention encompass both the precursors and the active forms of a protein encoded by clone AC012614_1.0.123.

MOL18 or 4339264-2

Clone 4339264-2 includes a polynucleotide having 1208 bp (SEQ ID NO: 153), shown in Table AAJ. This clone was isolated from lymph node, and is also found in MCF-

7, OVCAR-3, heart, prostate, uterus, mammary gland, salivary gland, thalamus, bone marrow, lymph node, spleen, fetal liver, fetal thymus - CRL7046, brain, fetal brain, liver, fetal liver, skeletal muscle, pancreas, kidney, heart, lung and placenta. Clone 4339264-2 includes an ORF encoding a polypeptide of 322 amino acid residues (SEQ ID NO: 154), shown in Table AAJ. The initiation codon is found at nucleotides 124-126 and the stop codon is at nucleotides 1090-1092. The PSORT program predicts that the protein localizes to the mitochondrial inner membrane with a certainty of 0.7515, or to the plasma membrane with a certainty of 0.6000. The SignalP program predicts that there may be a signal peptide, with the most likely cleavage site found between residues 59 and 60, represented by the dash between the amino acids VGA-WT (i.e., ValGlyAla-TrpThr). Table AAJ. Sequence of Clone 4339264-2.

Translated Protein - Nucleotide 124 to 1089

1 CTTTGCTTCAGCCGCAGTCGCCACTGGCTGCCTGAGGTGCTCTTA 46 CAGCCTGTTCCAAGTGTGGCTTAATCCGTCTCCACCACCAGATCT

91 TTCTCCGTGGATTCCTCTGCTAAGACCGCTGCCATGCCAGTGACG

MetProValThr

136 GTAACCCGCACCACCATCACAACCACCACGACGTCATCTTCGGGC ValThrArgThrThrlleThrT rThrThrT rSerSerSerGly

181 CTGGGGTCCCCCATGATCGTGGGGTCCCCTCGGGCCCTGACACAG LeuGlySerProMetlleValGlySerProArgAlaLeuThrGln

226 CCCCTGGGTCTCCTTCGCCTGCTGCAGCTGGTGTCTACCTGCGTG ProLeuGlyLeuLeuArgLeuLeuGlnLeuValSerThrCysVal 271 GCCTTCTCGCTGGTGGCTAGCGTGGGCGCCTGGACGGGGTCCATG AlaPheSerLeuValAlaSerValGlyAlaTrpThrGlySer et

316 GGCAACTGGTCCATGTTCACCTGGTGCTTCTGCTTCTCCGTGACC GlyAsnTrpSerMetPheT rTrpCysPheCysPheSerValT r

361 CTGATCATCCTCATCGTGGAGCTGTGCGGGCTCCAGGCCCGCTTC LeuIlelleLeuIleValGluLeuCysGlyLeuGlnAlaArgPhe

406 CCCCTGTCTTGGCGCAACTTCCCCATCACCTTCGCCTGCTATGCG ProLeuSerTrpArgAsnPheProIleThrPheAlaCysTyrAla

451 GCCCTCTTCTGCCTCTCGGCCTCCATCATCTACCCCACCACCTAT AlaLeuPheCysLeuSerAlaSerllelleTyrProThrThrTyr 496 GTCCAGTTCCTGTCCCACGGCCGTTCGCGGGACCACGCCATCGCC ValGlnPheLeuSerHisGlyArgSerArgAspHisAlalleAla 541 GCCACCTTCTTCTCCTGCATCGCGTGTGTGGCTTACGCCACCGAA AlaThrPhePheSerCysIleAlaCysValAlaTyrAlaThrGlu

586 GTGGCCTGGACCCGGGCCCGGCCCGGCGAGATCACTGGCTATATG ValAlaTrpThrArgAlaArgProGlyGluIleThrGlyTyrMet

631 GCCACCGTACCCGGGCTGCTGAAGGTGCTGGAGACCTTCGTTGCC AlaThrValProGlyLeuLeuLysValLeuGluThrPheValAla

676 TGCATCATCTTCGCGTTCATCAGCGACCCCAACCTGTACCAGCAC CysIlellePheAlaPhelleSerAspProAsnLeuTyrGlnHis

721 CAGCCGGCCCTGGAGTGGTGCGTGGCGGTGTACGCCATCTGCTTC GlnProAlaLeuGluTrpCysValAlaValTyrAlalleCysPhe

766 ATCCTAGCGGCCATCGCCATCCTGCTGAACCTGGGGGAGTGCACC IleLeuAlaAlalleAlalleLeuLeuAsnLeuGlyGluCysThr 811 AACGTGCTACCCATCCCCTTCCCCAGCTTCCTGTCGGGGCTGGCC AsnValLeuProIleProPheProSerP eLeuSerGlyLeuAla

856 TTGCTGTCTGTCCTCCTCTATGCCACCGCCCTTGTTCTCTGGCCC LeuLeuSerValLe LeuTyrAlaT rAlaLeuValLeuTrpPro

901 CTCTACCAGTTCGATGAGAAGTATGGCGGCCAGCCTCGGCGCTCG LeuTyrGlnPheAspGluLysTyrGlyGlyGlnProArgArgSer

946 AGAGATGTAAGCTGCAGCCGCAGCCATGCCTACTACGTGTGTGCC ArgAspValSerCysSerArgSerHisAlaTyrTyrValCysAla

991 TGGGACCGCCGACTGGCTGTGGCCATCCTGACGGCCATCAACCTA TrpAspArgArgLeuAlaValAlalleLeuThrAlalleAsnLeu 1036 CTGGCGTATGTGGCTGACCTGGTGCACTCTGCCCACCTGGTTTTT LeuAlaTyrValAlaAspLeuValHisSerAlaHisLeuValPhe

1081 GTCAAGGTCTAAGACTCTCCCAAGAGGCTCCCGTTCCCTCTCCAA ValLysVal

1126 CCTCTTTGTTCTTCTTGCCCGAGTTTTCTTTATGGAGTACTTCTT

1171 TCCTCCGCCTTTCCTCTGTTTTCCTCTTCCTGTCTCCC

BLASTX and BLASTP searches show that the protein has an 84 residue fragment that is 100% identical to a the same fragment in a protein encoded by a human EST sequence (PCT Publication WO 9906552-A2, published 1 l-FEB-1999). An additional BLASTN search showed that clone 4339264-2 is similar to murine mRNA for myeloid associated differentiation protein (GenBank-ID:MMMYELUPR| acc:AJ001616, submitted 15-SEP-1997). This gene is described as being expressed in a stage specific fashion during myeloid differentiation but absent in lymphoid cells.

BLASTP searches identified additional similarities to a 296 aa mouse myeloid upregulated protein (GenBank ACC:035682), and a 153 aa human T-lymphocyte maturation-associated protein (GenBank ACC:P21 145).

Clone 4339264-2 proteins include the full length protein encoded by the ORF disclosed herein, as well as any mature protein arising therefrom. Such a mature protein could be formed, for example, as a result of the removal of a signal peptide. Clone 4339264-2 also includes all fragments, analogs, homologs and derivatives of Clone 4339264-2. Thus the proteins ofthe invention encompass both the precursors and the active forms of 4339264-2, including, for example, a myeloid associated differentiation- like Clone 4339264-2 protein. MOL19 or 4357764-3 Clone 4357764-3 includes a polynucleotide of 1203 bp (SEQ ID NO: 155), shown in Table AAK. This clone was isolated from lymph node. The clone includes an ORF encoding a polypeptide of 142 amino acid residues (SEQ ID NO: 156), shown in Table AAK. The ORF begins with an initiation codon at nucleotides 587-589 of SEQ ID NO: 155 and ends with a stop codon at nucleotides 1013-1015. The PSORT program predicts that the protein is localized extracellularly with a certainty of 0.8200. SignalP predicts that there is a signal peptide present, with the most likely cleavage site found between residues 21 and 22, represented by the dash between the amino acids TRS-SE (i.e., ThrArgSer- SerGlu).

Table AAK .

A. Sequence of Clone 4357764-3. Translated Protein - Nucleotide 587 to 1012

1 GGAAGAAGAAGGAGGAGGAGGAGAAGGAGAAGAAGAAGGAGAAGA

46 ACGCAAGACTTCGTCTCAAAAAAAAAGAAGAAAAAATTTAAATAC

91 ATTTAAAAAAGAAGGTTGCATGCTGTGGAGCAACCAGACAATTGT 136 GATGAAATGTGAAGCACAAGGCACCAGCTGTGACGTGTTTTTGCC

181 AAGAAGTCAAACCACGTTCCAACTAAACCTCTAGAGCAAACTTTC

226 ATTTTCAGCAAATTCGAAGAAAAGAGGAATAATGTAAATGACCCC

271 ACAGGGAAACAGACAAACCCTGAATGTGGAGCATTTCACAGGACA

316 AAACCTGGACAGACATCGGAACACTTACAGGATGTGTGTAGTGTG 361 GCATGACAGAGAACTTTGGTTTCCTTTAATGTGACTGTAGACCTG

406 GCAGTGTTACTATAAGAATCACTGGCAATCAGACACCCGGGTGTG 451 CTGAGCTGGCACTCAGTGGGGGCGGCTACTGCTCATGTGATTGTG 496 GAGTAGACAGTTGGAAGAAGTACCCAGTCCATTTGGAGAGTTAAA 541 ACTGTGCCTAACAGAGGTGTCCTCTGACTTTTCTTCTGCAAGCTC

586 CATGTTTTCACATCTTCCCTTTGACTGTGTCCTGCTGCTGCTGCT

MetPheSerHisLeuProPheAspCysValLeuLeu euLeuLe 631 GCTACTACTTACAAGGTCCTCAGAAGTGGAATACAGAGCGGAGGT uLeuLeuLeuThrArgSerSerGluValGluTyrArgAlaGluVa

676 CGGTCAGAATGCCTATCTGCCCTGCTTCTACACCCCAGCCGCCCC lGlyGlnAsnAlaTyrLeuProCysPheTyrThrProAlaAlaPr

721 AGGGAACCTCGTGCCCGTCTGCTGGGGCAAAGGAGCCTGTCCTGT oGlyAsnLeuValProValCysTrpGlyLysGlyAlaCysProVa

766 GTTTGAATGTGGCAACGTGGTGCTCAGGACTGATGAAAGGGATGT 1PheGluCysGlyAsnValValLeuArgThrAspGluArgAspVa

811 GAATTATTGGACATCCAGATACTGGCTAAATGGGGATTTCCGCAA lAsnTyrTrpThrSerArgTyrTrpLeuAsnGlyAspPheArgLy 856 AGGAGATGTGTCCCTGACCATAGAGAATGTGACTCTAGCAGACAG sGlyAspValSerLeuThrlleGluAsnValThrLeuAlaAspSe

901 TGGGATCTACTGCTGCCGGATCCAAATCCCAGGCATAATGAATGA rGlylleTyrCysCysArglleGlnlleProGlylleMetAsnAs

946 TGAAAAATTTAACCTGAAGTTGGTCATCAAACCAGGTGAGTGGAC pGluLysPheAsnLeuLysLeuVallleLysProGlyGluTrpTh

991 ATTTGCATGCCATCTTTATGAATAAGATTTATCTGTGGATCATAT rPheAlaCysHisLeuTyrGlu

1036 TAAAGGTACTGATTGTTCTCATCTCTGACTTCCCTAATTATAGCC

1081 CTGGAGGAGGGCCACTAAGACCTAAAGTTTAACAGGCCCCATTGG

1126 TGATGCTCAGTGATATTTAACACCTTCTCTCTGTTTTAAAACTCA 1171 TGGGTGTGCCTGGGCGTGGTGGCTCACACCTCT

BLASTX analysis showed that, over 135 residues, the polypeptide encoded by clone 4357764-3 is 97% identical and 98% positive with the 301 residue protein encoded by human "200 gene" that is reported to be differentially expressed in T helper cells (U.S. Patent 5,721,351; PCT Publication WO 9627603-AI, published 12-SEP-1996). The 200 gene protein is reported to be a novel cell surface receptor ofthe Ig superfamily class. Expression of 200 gene is many-fold higher in TH1 than in TH2 subpopulations (WO9627603-A1). Modulation ofthe 200 gene product may ameliorate a range of T-cell- related disorders. BLASTP searches also show a moderate degree of similarity to kidney injury molecule- 1 ofthe rat (GenBank acc:054947) and to human hepatitis A virus cellular receptor 1 (GenBank acc:043656).

Clone 4357764-3 proteins include the full length protein encoded by the ORF disclosed herein, as well as any mature protein arising therefrom. Such a mature protein could be formed, for example, as a result ofthe removal of a signal peptide. Clone 4357764-3 also includes all fragments, analogs, homologs and derivatives of Clone 4357764-3. Thus the proteins ofthe invention encompass both the precursors and the active forms of a protein encoded by clone 4339264-3.

Other variants are shown below in Tables ABR and ABS. (4339264-3 is also known as CG52676-02.)

Table ABR

Polypeptide and Polynucleotide Sequence of Clone 191998702

Polynucleotide (SEQ ID NO: 157) Polypeptide (SEQ ID NO: 158)

DNA Sequence Analysis of 191998702

Translated Protein - Frame 1 - Nycleofide 1 to 375

Printed 80 characters to a line

AAGCTTTC^σ s^GTGGAAT CAG^GCσG^ή.GGTCGGTCAG ATGCCTATCTGCCCTGCTTCT^C^CCCCAGCCGCCCCAGG

E Y R

GAACCTCGTGCCCGTCTGCTGGGGCAAAGGAGCCTGTCCTGTGTTTGAnTGTGGCAACGTGGTGCTCAGGACTGATGAAA

V C W A C P V N V V L

GGGATGTGAATTATTGGACATCCAGATACTGGCTAAATGGGGATTTCCGCAAAGGAGATGTGTCCCTGACCATAGAGAAT

V N Y Y w

GTG CTCTAGCaGACAGTGGGATCTACTGCTGCCGGATCC AAATCCCAGGC AiTAATG AATGATGAAAAATTTAACCTGAA

241 V T A D S G I Y C C Q I

GTTGGTCATCAAnCCAGGTGAGTGGACATTTGCATGCCATCTTTATGAACTCGAG L V I K P G E W T F A C H L Y E L E

Table ABS

Alignment of Polypeptide Sequence of Clone 191998702 (SEQ ID

NO: 158) with Polypeptide Sequence of CG52676-02 (SEQ ID

NO:156)

1 1 98702 42 ECGNWL RTD ER DVNYWTSRYWLNGDFR GDVSLT I ENWLADSG I CCR I Q I PG I WIN

CGS2676-02 61 ECGNWLRTDE R DVNYWTSRYWLNGDF RKGDVSLTI ENVTLADSG IYCCR I Q I PG I WIN

191998702 ] 02 KF N LK LV I K PGEWT FAC HLYE L

CG52676-02 121 MJϋMVJiadttt l ϊTHilE'I: MOL20 or 4391184

Clone 4391184 is a polynucleotide of 825 bp (SEQ ID NO: 159), shown in Table AAL. This clone was isolated from lymph node tissue. Clone 4391184 contains an ORF encoding a protein of 92 amino acid residues (SEQ ID NO: 160), shown in Table AAL. The start codon is at nucleotides 494-496 and the stop codon is at nucleotides 770-772. The PSORT program predicts that the protein of clone 4391 184 localizes to the microbody (peroxisome) with a certainty of 0.5690. The SignalP software program predicts a low likelihood ofthe protein including a known signal peptide. Table AAL . Sequence of Clone 4391184 .

Translated Protein - Nucleotide 494 to 769

1 TCTAGAACATTCTCCAGCCCTTTTTTTCTTTTGCTCTTTTATGAC 46 ATTGACATGAAGAGTCCGGGCCAGTTGTTCTGGATTTGTCTGATT

91 GCTTCTCCCTGGTTGGAGTCAGGTGGAACAGCTCTGGCAGGAACG

136 CCCCCCCGGGCAATGCAGAGTCCTCCTCCAGGAGGCACTTAGTGT

181 CCATGCGTCACCTTGCTGGTGATGCTTCACTGGATCACTTGGTTC

226 CGGGGTTGTCCGCACGTCTCCCTGTAGTGCAGGTGCTCCTTCCTC 271 TTTCCAATTAGCCTGTGGGATGGGACTTGGAAGCTGTGTCTGTTC

316 TGCTCCACTGGCAACCTTTTCTTCAATGACTTAAGCTGGTGTTTT

361 GCCATTTTCCATACTCTATCATGGGGAGTGTTCAGTATCGGCATC

406 TAGAGATCTCCCCTGGCCCCATCACAGCTAGAGCTATGCTGTCCC 451 CTTTCAGGGACATCTTGTAATTTATCCACCCAGCCCCCAACTGAT

Me

496 GGACATAAAGGCTGTCTCCCCATCATCTCCTGCTACTACAGACAG tAspIleLysAlaValSerProSerSerProAlaThrThrAspSe

541 CACTGCAGGGACTGTCCTGCTGTGTTTTTTTAAGGCATGGGTACT rThrAlaGlyThrVa1LeuLeuCysPhePheLysAlaTrpVa1Le

586 CCAGAAGCAGTTGCTCAGCTGCACCCCCAAGGTTGAGTGGAAGTC uGlnLysGlnLeuLeuSerCysThrProLysValGluTrpLysSe

631 CCTCGGTAAAGGAGGAGGAGAGAGTGTGAAGGGAATGGCAAGGCG rLeuGlyLysGlyGlyGlyGluSerValLysGlyMetAlaArgAr 676 GGGAGGGAGACAGGGCACAGGTGTCCTGGCAACAGCAGATGGGAA gGlyGlyArgGlnGlyThrGlyValLeuAlaThrAlaAspGlyLy

721 ACAGGTCTGGCTAAGGTACCAGAAGCCAACAAGTCCCAGAAAGGT sGlnValTrpLeuArgTyrGlnLysProThrSerProArgLysVa

766 CAAGTGACTTTCCCAAGGTCACACAGCAAGTTGATGGCAGAGCTG lLys 811 GGTACAGGACTCAGA

BLASTP searching revealed a similarity of Clone 4391184 to a fragment of human superoxide dismutase (Cu, Zn) (GenBank ACC:Q16839). Clone 4391 184 proteins include the full length protein encoded by the ORF disclosed herein, as well as any mature protein arising therefrom. Such a mature protein could be formed, for example, as a result ofthe removal of a signal peptide. Clone 4391184 also includes all fragments, analogs, homologs and derivatives of Clone 4391 184. Thus the proteins ofthe invention encompass both the precursors and the active forms of a protein encoded by clone 4391184. MOL21 or 4437909.0.4

Clone 4437909.0.4 was originally identified by Applicant as clone 4437909 in US Provisional application Serial No. 60/128,514. Clone 4437909.0.4 includes a polynucleotide of 1099 bp (SEQ ID NO: 161), shown in Table AAM. This clone has been found in osteogenic sarcoma cell lines - HTB96, adrenal gland, thalamus, fetal brain and fetal lung. Clone 4437909.0.4 includes an ORF encoding a polypeptide of 269 amino acid residues (SEQ ID NO: 162), shown in Table AAM. The initiation codon for this polypeptide occurs at nucleotides 83-85 of SEQ ID NO: 161 and the termination codon is at nucleotides 890-892. The PSORT program predicts that the 4437909.0.4 protein is localized in the microbody (peroxisome) with a certainty of 0.7480. The SignalP program predicts that there is no known signal peptide.

Table AAM. Sequence of Clone 4437909.0.4 Translated Protein -Nucleotide 83 to 889

1 CTAGAATTCAGCGGCCGCTGAATTCTAGTGCAGAGTGAGCAAGGG

46 CCGCCTCATCCAGCTTCTCTCTGAGAGCCAGGGCCACATGGCTCA MetAlaHi

91 CCTGGTGAACTCCGTCAGCGACATCCTGGATGCCCTGCAGAGGGA sLeuValAsnSerValSerAspIleLeuAspAlaLeuGlnArgAs 136 CCGGGGGCTGGGCCGGCCCCGCAACAAGGCCGACCTTCAGAGAGC pArgGlyLeuGlyArgProArgAsnLysAlaAspLeuGlnArgAl

181 GCCTGCCCGGGGAACCCGGCCCCGGGGCTGTGCCACTGGCTCCCG aProAlaArgGlyThrArgProArgGlyCysAlaThrGlySerAr

226 GCCCCGAGACTGTCTGGACGTCCTCCTAAGCGGACAGCAGGACGA gProArgAspCysLeuAspValLeuLeuSerGlyGlnGlnAspAs

271 TGGCGTCTACTCTGTCTTTCCCACCCACTACCCGGCCGGCTTCCA pGlyValTyrSerValPheProThrHisTyrProAlaGlyPheGl

316 GGTGTACTGTGACATGCGCACGGACGGCGGCGGCTGGACGGTGTT nValTyrCysAspMetArgThrAspGlyGlyGlyTrpThrValPh

361 TCAGCGCCGGGAGGACGGCTCCGTGAACTTCTTCCGGGGCTGGGA eGlnArgArgGluAspGlySerValAsnPhePheArgGlyTrpAs

406 TGCGTACCGAGACGGCTTTGGCAGGCTCACCGGGGAGCACTGGCT pAlaTyrArgAspGlyPheGlyArgLeuThrGlyGluHisTrpLe 451 AGGGCTCAAGAGGATCCACGCCCTGACCACACAGGCTGCCTACGA uGlyLeuLysArg11eHisAlaLeuThrThrGlnAlaAlaTyrGl

496 GCTGCACGTGGACCTGGAGGACTTTGAGAATGGCACGGCCTATGC uLeuHisValAspLeuGluAspPheGluAsnGlyThrAlaTyrAl

541 CCGCTACGGGAGCTTCGGCGTGGGCTTGTTCTCCGTGGACCCTGA aArgTyrGlySerPheGlyValGlyLeuPheSerValAspProGl

586 GGAAGACGGGTACCCGCTCACCGTGGCTGACTATTCCGGCACTGC uGluAspGlyTyrProLeuThrValAlaAspTyrSerGlyThrAl

631 AGGCGACTCCCTCCTGAAGCACAGCGGCATGAGGTTCACCACCAA aGlyAspSerLeuLeuLysHisSerGlyMetArgPheThrThrLy 676 GGACCGTGACAGCGACCATTCAGAGAACAACTGTGCCGCCTTCTA sAspArgAspSerAspHisSerGluAsnAsnCysAlaAlaPheTy

721 CCGCGGTGCCTGGTGGTACCGCAACTGCCACACGTCCAACCTCAA rArgGlyAlaTrpTrpTyrArgAsnCysHisThrSerAsnLeuAs

766 TGGGCAGTACCTGCGCGGTGCGCACGCCTCCTATGCCGACGGCGT nGlyGlnTyrLeuArgGlyAlaHisAlaSerTyrAlaAspGlyVa

811 GGAGTGGTCCTCCTGGACCGGCTGGCAGTACTCACTCAAGTTCTC lGluTrpSerSerTrpThrGlyTrpGlnTyrSerLeuLysPheSe

856 TGAGATGAAGATCCGGCCGGTCCGGGAGGACCGCTAGACCGGTGC rGluMetLysIleArgProValArgGluAspArg 901 ACCTTGTCCTTGGCCCTGCTGGTCCCTGTCGCCCCATCCCCGACC

946 CCACCTCACTCTTTCGTGAATGTTCTCCACCCACCTGTGCCTGGC

991 GGACCCACTCTCCAGTAGGGAGGGGCCGGGCCATCCCTGACACGA

1036 AGCTCCCTGGGCCGGTGAAGTCACACATCGCCTTCTCGCCGTCCC 1081 CACCCCCTCCATTTGGCAG

BLASTP and BLASTX searching showed that the 4437909.0.4 polypeptide has a

55% identity and a 70% similarity to the 255 residue human microfibril-associated glycoprotein 4 (ACC:P55083 and US Patent No. 5972654-A, issued 26-OCT-1999). The human microfibril-associated glycoprotein 4 splice variant (MAG4V) polypeptides and/or antibodies thereto are disclosed in this patent as being usable to down regulate MAG4V expression and activity. By analogy, Clone 4437909.0.4 polypeptides as well as MAG4V proteins may be used to treat reproductive disorders (e.g. disruptions o the estrous cycle and spermatogenesis, polycystic ovary syndrome and cancers ofthe prostate and ovaries), muscular disorders (e.g. Duchenne's muscular dystrophy, lipid myopathy and myocarditis), immunological disorders (e.g. Addison's disease, asthma, anemia and acquired immune deficiency syndrome (AIDS)) and neoplastic disorders (e.g. myeloma, sarcoma, leukemia and lung cancer).

BLASTX searching further showed that the 4437909.0.4 protein is 48% identical and 61%) positive with the 313 residue human 35 kDa opsonin protein P35 (JP08038182- A, published 13-FEB-1996). P35 protein has opsonin activity useful in prevention and treatment of infectious diseases. Opsonin activates the phagocytosis of pathogenic microbes by phagocytic cells, useful in the prevention and treatment of infectious diseases. By analogy, Clone 4437909.0.4 may also be utilized in the prevention and treatment of infectious diseases. Additionally the 4437909.0.4 protein, over 221 residues, is also 52% identical and 63% similar to the 324 residue porcine TGF-beta- 1 binding protein (W09222319-A), and Clone 4437909.0.4 protein may additionally have TGF-beta-1 binding activity.

Clone 4437909.0.4 proteins include the full length protein encoded by the 4437909.0.4 ORF disclosed herein, as well as any mature protein arising therefrom. Such a mature protein could be formed, for example, as a result of he removal of a signal peptide. Clone 4437909.0.4 also includes all fragments, analogs, homologs and derivatives of Clone 4437909.0.4. Thus the proteins ofthe invention encompass both the precursors and the active forms of a protein encoded by clone 4437909.0.4. Clone 4437909.0.4 activities may include those activities possessed by MAG4V protein or opsonin P35 protein. MOL22 or 4437909.0.55

Clone 4437909.0.55 is a variant of clone 4437909.0.4, and has a shorter 5' UTR and two base changes in the coding sequence.

Clone 4437909.0.55 has 1054 bp (SEQ ID NO: 163), shown in Table AAN. This clone has been found in osteogenic sarcoma cell lines - HTB96, adrenal gland, thalamus, fetal brain and fetal lung. This clone includes an ORF beginning at nucleotides 38-40 and terminating at nucleotides 845-847, encoding a polypeptide of 269 amino acid residues (SEQ ID NO: 164), shown in Table AAN. The mutations in the open reading frame lead to two mutated amino acid residues. The properties and physiological activities of clone 4437909.0.55 are essentially the same as those summarized above for clone 4437909.0.4 Table AAN. Sequence of Clone 4437909 . 0 . 55

Translated Protein - Frame: 2 - Nucleotide 38 to 844 1

CCGCCTCATCCAGCTTCTCTCTGAGAGCCAGGGCCACATGGCTCA

MetAlaHi 46

CCTGGTGAACTCCGTCAGCGACATCCTGGATGCCCTGCAGAGGGA sLeuValAsnSerValSerAspIleLeuAspAlaLeuGlnArgAs 91

CCGGGGGCTGGGCCGGCCCCGCAACAAGGCCGACCTTCAGAGAGC pArgGlyLeuGlyArgProArgAsnLysAlaAspLeuGlnArgAl

136 GCCTGCCCGGGGAACCCGGCCCCGGGGCTGTGCCACTGGCTCCCG aProAlaArgGlyThrArgProArgGlyCysAlaThrGlySerAr

181

GCCCCGAGACTGTCTGGACGTCCTCCTAAGCGGACAGCAGGACGA gProArgAspCysLeuAspValLeuLeuSerGlyGlnGlnAspAs 226

TGGCGTCTACTCTGTCTTTCCCACCCACTACCCGGCCGGCTTCCA pGlyValTyrSerValPheProThrHisTyrProAlaGlyPheGl 271

GGTGTACTGTGACATGCGCACGGACGGCGGCGGCTGGACGGTGTT nValTyrCysAspMetArgThrAspGlyGlyGlyTrpThrValPh 316

TCAGCGCCGGGAGGACGGCTCCGTGAACTTCTTCCGGGGCTGGGA eGlnArgArgGluAspGlySerValAsnPhePheArgGlyTrpAs

361 TGCGTACCGAGACGGCTTTGGCAGGCTCACCGGGGAGCACTGGCT pAlaTyrArgAspGlyPheGlyArgLeuThrGlyGluHisTrpLe

406

AGGGCTCAAGAGGATCCACGCCCTGACCACACAGGCTGCCTACGA uGlyLeuLysArglleHisAlaLeuThrThrGlnAlaAlaTyrGl 451

GCTGCACGTGGACCTGGAGGACTTTGAGAATGGCACGGCCTATGC uLeuHisValAspLeuGluAspPheGluAsnGlyThrAlaTyrAl 496

CCGCTACGGGAGCTTCGGCGTGGGCTTGTTCGCCGTGGACCCTGA aArgTyrGlySerPheGlyValGlyLeuPheAlaValAspProGl 541

GGAAGACGGGCACCCGCTCACCGTGGCTGACTATTCCGGCACTGC uGluAspGlyHisProLeuThrValAlaAspTyrSerGlyThrAl 586

AGGCGACTCCCTCCTGAAGCACAGCGGCATGAGGTTCACCACCAA aGlyAspSerLeuLeuLysHisSerGlyMetArgPheThrThrLy 631

GGACCGTGACAGCGACCATTCAGAGAACAACTGTGCCGCCTTCTA sAspArgAspSerAspHisSerGluAsnAsnCysAlaAlaPheTy

676 CCGCGGTGCCTGGTGGTACCGCAACTGCCACACGTCCAACCTCAA rArgGlyAlaTrpTrpTyrArgAsnCysHisThrSerAsnLeuAs

721

TGGGCAGTACCTGCGCGGTGCGCACGCCTCCTATGCCGACGGCGT nGlyGlnTyrLeuArgGlyAlaHisAlaSerTyrAlaAspGlyVa 766

GGAGTGGTCCTCCTGGACCGGCTGGCAGTACTCACTCAAGTTCTC lGluTrpSerSerTrpThrGlyTrpGlnTyrSerLeuLysPheSe 811

TGAGATGAAGATCCGGCCGGTCCGGGAGGACCGCTAGACCGGTGC rGluMetLysIleArgProValArgGluAspArg 856

ACCTTGTCCTTGGCCCTGCTGGTCCCTGTCGCCCCATCCCCGACC 901

CCACCTCACTCTTTCGTGAATGTTCTCCACCCACCTGTGCCTGGC 946

GGACCCACTCTCCAGTAGGGAGGGGCCGGGCCATCCCTGACACGA 991

AGCTCCCTGGGCCGGTGAAGTCACACATCGCCTTCTCGCCGTCCC 1036 CACCCCCTCCATTTGGCAG

Clone 4437909.0.55 proteins include the full length protein encoded by the 4437909.0.55 ORF disclosed herein, as well as any mature protein arising therefrom. Such a mature protein could be formed, for example, as a result ofthe removal of a signal peptide. Clone 4437909.0.55 also includes all fragments, analogs, homologs and derivatives of Clone 4437909.0.55. Thus the proteins ofthe invention encompass both the precursors and the active forms of a protein encoded by clone 4437909.0.55. Clone 4437909.0.55 activities may include those activities possessed by MAG4V protein or opsonin P35 protein. The construct is called TA-4437909-S443. The coding sequence in clone TA-

4437909-S443 differs by one bp from that given for clone 4437909.0.4 (Table AAR; SEQ ID NO:165). The sequence of clone TA-4437909-S443 (SEQ ID NO: 165) is shown in Table AAR, and the variant base is underlined. The base change, however, is silent and does not change the polypeptide sequence (SEQ ID NO: 164) predicted for clone 4437909.0.4. Table AAR . Sequence of Clone TA-4437909-S443

CAGAGAGCGCCTGCCCGGGGAACCCGGCCCCGGGGCTGTGCCACTGGCTCCCGGCCCCGAGAC TGTCTGGACGTCCTCCTAAGCGGACAGCAGGACGATGGCGTCTACTCTGTCTTTCCCACCCACT ACCCGGCCGGCTTCCAGGTGTACTGTGACATGCGCACGGACGGCGGCGGCTGGACGGTGTTTC AGCGCCGGGAGGACGGCTCCGTGAACTTCTTCCGGGGCTGGGACGCGTACCGAGACGGCTTTG GCAGGCTCACCGGGGAGCACTGGCTAGGGCTCAAGAGGATCCACGCCCTGACCACACAGGCTG CCTACGAGCTGCACGTGGACCTGGAGGACTTTGAGAATGGCACGGCCTATGCCCGCTACGGGA GCTTCGGCGTGGGCTTGTTCGCCGTGGACCCTGAGGAAGACGGGTACCCGCTCACCGTGGCTG ACTATTCCGGCACTGCAGGCGACTCCCTCCTGAAGCACAGCGGCATGAGGTTCACCACCAAGG ACCGTGACAGCGACCATTCAGAGAACAACTGTGCCGCCTTCTACCGCGGTGCCTGGTGGTACC GCAACTGCCACACGTCCAACCTCAATGGGCAGTACCTGCGCGGTGCGCACGCCTCCTATGCCG ACGGCGTGGAGTGGTCCTCCTGGACCGGCTGGCAGTACTCACTCAAGTTCTCTGAGATGAAGAT CCGGCCGGTCCGG GAGGACCGC (SEQ ID NO:XX)

MOL23 or CG52703-03

Clone CG52703-03 has 1037 bp, and the polynucleotide (SEQ ID NO: 166) and polypeptide (SEQ ID NO: 167) are given at Tables ACA and ACB. The polynucleotide sequence encodes a microfibril-associated glycoprotein-like protein. An open reading frame was identified beginning at nucleotides 46-48 and ending at nucleotides 853-855. The encoded polypeptide has 269 amino acid residues, and is presented in FIG. 26 using the one letter codes. CG52703-03 has greater than 65% nucleic acid identity to human microfibril associated glucoprotein 4, and has greater than 55% identity to the same protein. The polypeptide displays at least one fibrinogen beta and gamma chains C- terminal globular domain, and thus has properties similar to those of other proteins known to contain these domains. The nucleic acid maps to chromosome 9. Expression ofthe gene has been detected in at least the following tissues: adrenal/supraadrenal gland, salivary gland, liver, bone marrow, lymphoid tissue, hippocampus, lung, thalamus, amygdala, placenta and hair follicles. The polypeptide is localized to peroxisomal bodies and is also secreted. The protein has structural and physiological functions similar to those ofthe microfibril associated glycoprotein family. Clone CG52703-03 activities include those activities possessed by microfibril associated glycoprotein families, and accordingly, is useful in serving as a diagnostic or prognostic marker for the diseases indicated herein. Potential therapeutic applications include protein therapeutics, small molecule targets, antibody targets, nucleic acids useful in gene therapy, and the like. Table ACA CG52703-03

AGCAAGGGCCGCCTCATCCAGCTTCTCTCTGAGAGCCAGGCCCACATGGCTCACCTGGTG 60

AACTCCGTCAGCGACATCCTGGATGCCCTGCAGAGGGACCGGGGGCTGGGCCGGCCCCGC 120

AACAAGGCCGACCTTCAGAGAGCGCCTGCCCGGGGAACCCGGCCCCGGGGCTGTGCCACT 180 GGCTCCCGGCCCCGAGACTGTCTGGACGTCCTCCTAAGCGGACAGCAGGACGATGGCGTC 240

TACTCTGTCTTTCCCACCCACTACCCGGCCGGCTTCCAGGTGTACTGTGACATGCGCACG 300

GACGGCGGCGGCTGGACGGTGTTTCAGCGCCGGGAGGACGGCTCCGTGAACTTCTTCCGG 360

GGCTGGGATGCGTACCGAGACGGCTTTGGCAGGCTCACCGGGGAGCACTGGCTAGGGCTC 420

AAGAGGATCCACGCCCTGACCACACAGGCTGCCTACGAGCTGCACGTGGACCTGGAGGAC 480 TTTGAGAATGGCACGGCCTATGCCCGCTACGGGAGCTTCGGCGTGGGCTTGTTCTCCGTG 540

GACCCTGAGGAAGACGGGTACCCGCTCACCGTGGCTGACTATTCCGGCACTGCAGGCGAC 600

TCCCTCCTGAAGCACAGCGGCATGAGGTTCACCACCAAGGACCGTGACAGCGACCATTCA 660

GAGAACAACTGTGCCGCCTTCTACCGCGGTGCCTGGTGGTACCGCAACTGCCACACGTCC 720

AACCTCAATGGGCAGTACCTGCGCGGTGCGCACGCCTCCTATGCCGACGGCGTGGAGTGG 780 TCCTCCTGGACCGGCTGGCAGTACTCACTCAAGTTCTCTGAGATGAAGATCCGGCCGGTC 840

CGGGAGGACCGCTAGACTGGTGCACCTTGTCCTTGGCCCTGCTGGTCCCTGTCGCCCCAT 900

CCCCGACCCCACCTCACTCTTTCGTGAATGTTCTCCACCCACCTGTGCCTGGCGGACCCA 960

CTCTCCAGTAGGGAGGGGCCGGGCCATCCCTGACACGAAGCTCCCTGGGCCGGTGAAGTC 1020

ACACATCGCCTTCTCGC

Table ACB

>CG52703-03

MAHLTOSVSDI DALQRDRGLGRPRNKADLQRAPARGTRPRGCATGSRPRDCLDV LSGQ 60

QDDGVYSVFPTHYPAGFQVYCDMRTDGGG TVFQRREDGSVNFFRG DAYRDGFGR TGE 120 H LGLKRIHALTTQAAYELHVDLEDFENGTAYARYGSFGVG FSVDPEEDGYP TVADYS 180

GTAGDSLLKHSG RFTTKDRDSDHSENNCAAFYRGAW YRNCHTSNLNGQYLRGAHASYA 240

DGVE SSWTG QYS FSEMKIRPVREDR 269

Clone CG52703-03 proteins include the full length protein encoded by the CG52703-03 ORF disclosed herein, as well as any mature protein arising therefrom. Such a mature protein could be formed, for example, as a result ofthe removal of a signal peptide. Clone CG52703-03 also includes all fragments, analogs, homologs and derivatives of Clone CG52703-03. Thus the proteins ofthe invention encompass both the precursors and the active forms of a protein encoded by clone CG52703-03.

MOLX Nucleic Acids and Polypeptides

One aspect of he invention pertains to isolated nucleic acid molecules that encode MOLX polypeptides or biologically active portions thereof. Also included in the invention are nucleic acid fragments sufficient for use as hybridization probes to identify MOLX-encoding nucleic acids (e.g., MOLX mRNAs) and fragments for use as PCR primers for the amplification and/or mutation of MOLX nucleic acid molecules. As used herein, the term "nucleic acid molecule" is intended to include DNA molecules (e.g., cDNA or genomic DNA), RNA molecules (e.g., mRNA), analogs ofthe DNA or RNA generated using nucleotide analogs, and derivatives, fragments and homologs thereof. The nucleic acid molecule may be single-stranded or double-stranded, but preferably is comprised double-stranded DNA.

An MOLX nucleic acid can encode a mature MOLX polypeptide. As used herein, a "mature" form of a polypeptide or protein disclosed in the present invention is the product of a naturally occurring polypeptide or precursor form or proprotein. The naturally occurring polypeptide, precursor or proprotein includes, by way of nonlimiting example, the full-length gene product, encoded by the corresponding gene. Alternatively, it may be defined as the polypeptide, precursor or proprotein encoded by an ORF described herein. The product "mature" form arises, again by way of nonlimiting example, as a result of one or more naturally occurring processing steps as they may take place within the cell, or host cell, in which the gene product arises. Examples of such processing steps leading to a "mature" form of a polypeptide or protein include the cleavage ofthe N-terminal methionine residue encoded by the initiation codon of an ORF, or the proteolytic cleavage of a signal peptide or leader sequence. Thus a mature form arising from a precursor polypeptide or protein that has residues 1 to N, where residue 1 is the N-terminal methionine, would have residues 2 through N remaining after removal of the N-terminal methionine. Alternatively, a mature form arising from a precursor polypeptide or protein having residues 1 to N, in which an N-terminal signal sequence from residue 1 to residue M is cleaved, would have the residues from residue M+l to residue N remaining. Further as used herein, a "mature" form of a polypeptide or protein may arise from a step of post-translational modification other than a proteolytic cleavage event. Such additional processes include, by way of non-limiting example, glycosylation, myristoylation or phosphorylation. In general, a mature polypeptide or protein may result from the operation of only one of these processes, or a combination of any of them.

The term "probes", as utilized herein, refers to nucleic acid sequences of variable length, preferably between at least about 10 nucleotides (nt), 100 nt, or as many as approximately, e.g., 6,000 nt, depending upon the specific use. Probes are used in the detection of identical, similar, or complementary nucleic acid sequences. Longer length probes are generally obtained from a natural or recombinant source, are highly specific, and much slower to hybridize than shorter-length oligomer probes. Probes may be single- or double-stranded and designed to have specificity in PCR, membrane-based hybridization technologies, or ELISA-like technologies.

The term "isolated" nucleic acid molecule, as utilized herein, is one, which is separated from other nucleic acid molecules which are present in the natural source ofthe nucleic acid. Preferably, an "isolated" nucleic acid is free of sequences which naturally flank the nucleic acid (i.e., sequences located at the 5'- and 3'-termini ofthe nucleic acid) in the genomic DNA ofthe organism from which the nucleic acid is derived. For example, in various embodiments, the isolated MOLX nucleic acid molecules can contain less than about 5 kb, 4 kb, 3 kb, 2 kb, 1 kb, 0.5 kb or 0.1 kb of nucleotide sequences which naturally flank the nucleic acid molecule in genomic DNA ofthe cell/tissue from which the nucleic acid is derived (e.g., brain, heart, liver, spleen, etc.). Moreover, an "isolated" nucleic acid molecule, such as a cDNA molecule, can be substantially free of other cellular material or culture medium when produced by recombinant techniques, or of chemical precursors or other chemicals when chemically synthesized.

A nucleic acid molecule ofthe invention, e.g., a nucleic acid molecule having the nucleotide sequence of SEQ ID NOS: 1, 3, 5, 7, 9, 1 1 , 13, 15, 17, 19, 21, 23, 101, 103, 105, 107, 109, 1 12, 1 15, 1 17, 1 19, 121, 124, 135, 137, 139, 141, 143, 145, 147, 149, 151 , 153, 155, 157, 159, 161, 163, 165, and 166, or a complement of this aforementioned nucleotide sequence, can be isolated using standard molecular biology techniques and the sequence information provided herein. Using all or a portion ofthe nucleic acid sequence of SEQ ID NOS: l, 3, 5, 7, 9, 1 1, 13, 15, 17, 19, 21 , 23, 101, 103, 105, 107, 109, 1 12, 1 15, 1 17, 119, 121 , 124, 135, 137, 139, 141 , 143, 145, 147, 149, 151, 153, 155, 157, 159, 161 , 163, 165, and 166 as a hybridization probe, MOLX molecules can be isolated using standard hybridization and cloning techniques (e.g., as described in Sambrook, et al, (eds.), MOLECULAR CLONING: A LABORATORY MANUAL 2^nd Ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, 1989; and Ausubel, et al, (eds.), CURRENT PROTOCOLS IN MOLECULAR BIOLOGY, John Wiley & Sons, New York, NY, 1993.)

A nucleic acid ofthe invention can be amplified using cDNA, mRNA or alternatively, genomic DNA, as a template and appropriate oligonucleotide primers according to standard PCR amplification techniques. The nucleic acid so amplified can be cloned into an appropriate vector and characterized by DNA sequence analysis. Furthermore, oligonucleotides corresponding to MOLX nucleotide sequences can be prepared by standard synthetic techniques, e.g., using an automated DNA synthesizer. As used herein, the term "oligonucleotide" refers to a series of linked nucleotide residues, which oligonucleotide has a sufficient number of nucleotide bases to be used in a PCR reaction. A short oligonucleotide sequence may be based on, or designed from, a genomic or cDNA sequence and is used to amplify, confirm, or reveal the presence of an identical, similar or complementary DNA or RNA in a particular cell or tissue. Oligonucleotides comprise portions of a nucleic acid sequence having about 10 nt, 50 nt, or 100 nt in length, preferably about 15 nt to 30 nt in length. In one embodiment ofthe invention, an oligonucleotide comprising a nucleic acid molecule less than 100 nt in length would further comprise at least 6 contiguous nucleotides of SEQ ID NOS:l, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 101, 103, 105, 107, 109, 1 12, 115, 1 17, 119, 121, 124, 135, 137, 139, 141, 143, 145, 147, 149, 151, 153, 155, 157, 159, 161, 163, 165, and 166, or a complement thereof. Oligonucleotides may be chemically synthesized and may also be used as probes.

In another embodiment, an isolated nucleic acid molecule ofthe invention comprises a nucleic acid molecule that is a complement ofthe nucleotide sequence shown in SEQ ID NOS: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 101 , 103, 105, 107, 109, 112, 1 15, 1 17, 1 19, 121, 124, 135, 137, 139, 141, 143, 145, 147, 149, 151, 153, 155, 157, 159, 161, 163, 165, and 166, or a portion of this nucleotide sequence (e.g., a fragment that can be used as a probe or primer or a fragment encoding a biologically-active portion of an MOLX polypeptide). A nucleic acid molecule that is complementary to the nucleotide sequence shown in SEQ ID NOS: 1, 3, 5, 7, 9, 1 1, 13, 15, 17, 19, 21, 23, 101, 103, 105, 107, 109, 112, 115, 117, 119, 121, 124, 135, 137, 139, 141, 143, 145, 147, 149, 151, 153,

155, 157, 159, 161, 163, 165, and 166 is one that is sufficiently complementary to the nucleotide sequence shown in SEQ ID NOS: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 101,

103, 105, 107, 109, 112, 115, 117, 119, 121, 124, 135, 137, 139, 141, 143, 145, 147, 149,

151, 153, 155, 157, 159, 161, 163, 165, and 166 that it can hydrogen bond with little or no mismatches to the nucleotide sequence shown SEQ ID NOS:l, 3, 5, 7, 9, 1 1, 13, 15, 17, 19, 21, 23, 101, 103, 105, 107, 109, 112, 1 15, 1 17, 1 19, 121, 124, 135, 137, 139, 141, 143, 145, 147, 149, 151, 153, 155, 157, 159, 161, 163, 165, and 166, thereby forming a stable duplex. As used herein, the term "complementary" refers to Watson-Crick or Hoogsteen base pairing between nucleotides units of a nucleic acid molecule, and the term "binding" means the physical or chemical interaction between two polypeptides or compounds or associated polypeptides or compounds or combinations thereof. Binding includes ionic, non-ionic, van der Waals, hydrophobic interactions, and the like. A physical interaction can be either direct or indirect. Indirect interactions may be through or due to the effects of another polypeptide or compound. Direct binding refers to interactions that do not take place through, or due to, the effect of another polypeptide or compound, but instead are without other substantial chemical intermediates.

Fragments provided herein are defined as sequences of at least 6 (contiguous) nucleic acids or at least 4 (contiguous) amino acids, a length sufficient to allow for specific hybridization in the case of nucleic acids or for specific recognition of an epitope in the case of amino acids, respectively, and are at most some portion less than a full length sequence. Fragments may be derived from any contiguous portion of a nucleic acid or amino acid sequence of choice. Derivatives are nucleic acid sequences or amino acid sequences formed from the native compounds either directly or by modification or partial substitution. Analogs are nucleic acid sequences or amino acid sequences that have a structure similar to, but not identical to, the native compound but differs from it in respect to certain components or side chains. Analogs may be synthetic or from a different evolutionary origin and may have a similar or opposite metabolic activity compared to wild type. Homologs are nucleic acid sequences or amino acid sequences of a particular gene that are derived from different species.

Derivatives and analogs may be full length or other than full length, if the derivative or analog contains a modified nucleic acid or amino acid, as described below. Derivatives or analogs ofthe nucleic acids or proteins ofthe invention include, but are not limited to, molecules comprising regions that are substantially homologous to the nucleic acids or proteins ofthe invention, in various embodiments, by at least about 70%, 80%, or

95%o identity (with a preferred identity of 80-95%) over a nucleic acid or amino acid sequence of identical size or when compared to an aligned sequence in which the alignment is done by a computer homology program known in the art, or whose encoding nucleic acid is capable of hybridizing to the complement of a sequence encoding the aforementioned proteins under stringent, moderately stringent, or low stringent conditions. See e.g. Ausubel, et al, CURRENT PROTOCOLS IN MOLECULAR BIOLOGY, John Wiley & Sons, New York, NY, 1993, and below. A "homologous nucleic acid sequence" or "homologous amino acid sequence," or variations thereof, refer to sequences characterized by a homology at the nucleotide level or amino acid level as discussed above. Homologous nucleotide sequences encode those sequences coding for isoforms of MOLX polypeptides. Isoforms can be expressed in different tissues ofthe same organism as a result of, for example, alternative splicing of RNA. Alternatively, isoforms can be encoded by different genes. In the invention, homologous nucleotide sequences include nucleotide sequences encoding for an MOLX polypeptide of species other than humans, including, but not limited to: vertebrates, and thus can include, e.g., frog, mouse, rat, rabbit, dog, cat cow, horse, and other organisms. Homologous nucleotide sequences also include, but are not limited to, naturally occurring allelic variations and mutations ofthe nucleotide sequences set forth herein. A homologous nucleotide sequence does not, however, include the exact nucleotide sequence encoding human MOLX protein. Homologous nucleic acid sequences include those nucleic acid sequences that encode conservative amino acid substitutions (see below) in SEQ ID NOS: 1, 3, 5, 7, 9, 1 1, 13, 15, 17, 19, 21, 23, 101, 103, 105, 107, 109, 112, 115, 1 17, 119, 121 , 124, 135, 137, 139, 141, 143, 145, 147, 149, 151, 153, 155, 157, 159, 161, 163, 165, and 166, as well as a polypeptide possessing MOLX biological activity. Various biological activities ofthe MOLX proteins are described below.

An MOLX polypeptide is encoded by the open reading frame ("ORF") of an MOLX nucleic acid. An ORF corresponds to a nucleotide sequence that could potentially be translated into a polypeptide. A stretch of nucleic acids comprising an ORF is uninterrupted by a stop codon. An ORF that represents the coding sequence for a full protein begins with an ATG "start" codon and terminates with one ofthe three "stop" codons, namely, TAA, TAG, or TGA. For the purposes of this invention, an ORF may be any part of a coding sequence, with or without a start codon, a stop codon, or both. For an ORF to be considered as a good candidate for coding for a bonafide cellular protein, a minimum size requirement is often set, e.g., a stretch of DNA that would encode a protein of 50 amino acids or more.

The nucleotide sequences determined from the cloning ofthe human MOLX genes allows for the generation of probes and primers designed for use in identifying and/or cloning MOLX homologues in other cell types, e.g. from other tissues, as well as MOLX homologues from other vertebrates. The probe/primer typically comprises substantially purified oligonucleotide. The oligonucleotide typically comprises a region of nucleotide sequence that hybridizes under stringent conditions to at least about 12, 25, 50, 100, 150, 200, 250, 300, 350 or 400 consecutive sense strand nucleotide sequence of SEQ ID

NOS: l, 3, 5, 7, 9, 1 1, 13, 15, 17, 19, 21, 23, 101, 103, 105, 107, 109, 112, 1 15, 117, 1 19, 121, 124, 135, 137, 139, 141, 143, 145, 147, 149, 151 , 153, 155, 157, 159, 161, 163, 165, and 166; or an anti-sense strand nucleotide sequence of SEQ ID NOST, 3, 5, 7, 9, 1 1 , 13, 15, 17, 19, 21, 23, 101, 103, 105, 107, 109, 1 12, 115, 1 17, 1 19, 121, 124, 135, 137, 139, 141, 143, 145, 147, 149, 151, 153, 155, 157, 159, 161, 163, 165, and 166; or of a naturally occurring mutant of SEQ ID NOS: l, 3, 5, 7, 9, 1 1, 13, 15, 17, 19, 21, 23, 101, 103, 105, 107, 109, 112, 115, 117, 1 19, 121, 124, 135, 137, 139, 141, 143, 145, 147, 149, 151, 153, 155, 157, 159, 161, 163, 165, and 166.

Probes based on the human MOLX nucleotide sequences can be used to detect transcripts or genomic sequences encoding the same or homologous proteins. In various embodiments, the probe further comprises a label group attached thereto, e.g. the label group can be a radioisotope, a fluorescent compound, an enzyme, or an enzyme co-factor. Such probes can be used as a part of a diagnostic test kit for identifying cells or tissues which mis-express an MOLX protein, such as by measuring a level of an MOLX-encoding nucleic acid in a sample of cells from a subject e.g., detecting MOLX mRNA levels or determining whether a genomic MOLX gene has been mutated or deleted.

"A polypeptide having a biologically-active portion of an MOLX polypeptide" refers to polypeptides exhibiting activity similar, but not necessarily identical to, an activity of a polypeptide ofthe invention, including mature forms, as measured in a particular biological assay, with or without dose dependency. A nucleic acid fragment encoding a "biologically-active portion of MOLX" can be prepared by isolating a portion SEQ ID NOS: l, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 101, 103, 105, 107, 109, 112, 1 15, 1 17, 119, 121, 124, 135, 137, 139, 141, 143, 145, 147, 149, 151, 153, 155, 157, 159, 161, 163, 165, and 166 that encodes a polypeptide having an MOLX biological activity (the biological activities ofthe MOLX proteins are described below), expressing the encoded portion of MOLX protein (e.g., by recombinant expression in vitro) and assessing the activity ofthe encoded portion of MOLX. MOLX Nucleic Acid and Polypeptide Variants

The invention further encompasses nucleic acid molecules that differ from the nucleotide sequences shown SEQ ID NOS: l, 3, 5, 7, 9, 1 1, 13, 15, 17, 19, 21, 23, 101, 103, 105, 107, 109, 1 12, 1 15, 1 17, 1 19, 121, 124, 135, 137, 139, 141, 143, 145, 147, 149, 151, 153, 155, 157, 159, 161, 163, 165, and 166 due to degeneracy ofthe genetic code and thus encode the same MOLX proteins as that encoded by the nucleotide sequences shown in SEQ ID NOS: 1, 3, 5, 7, 9, 1 1, 13, 15, 17, 19, 21, 23, 101, 103, 105, 107, 109, 112, 1 15, 117, 119, 121, 124, 135, 137, 139, 141, 143, 145, 147, 149, 151, 153, 155, 157, 159, 161, 163, 165, and 166. In another embodiment, an isolated nucleic acid molecule of the invention has a nucleotide sequence encoding a protein having an amino acid sequence shown in SEQ ID NOS:2, A, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 102, 104, 106, 108, 1 1 1, 1 14, 1 16, 1 18, 120, 123, 125, 136, 138, 140, 142, 144, 146, 148, 150, 152, 154, 156, 158, 160, 162, 164, and 167.

In addition to the human MOLX nucleotide sequences shown in SEQ ID NOS: 1, 3, 5, 7, 9, 11 , 13, 15, 17, 19, 21 , 23, 101, 103, 105, 107, 109, 1 12, 115, 1 17, 119, 121 , 124, 135, 137, 139, 141, 143, 145, 147, 149, 151, 153, 155, 157, 159, 161, 163, 165, and 166 it will be appreciated by those skilled in the art that DNA sequence polymorphisms that lead to changes in the amino acid sequences ofthe MOLX polypeptides may exist within a population (e.g., the human population). Such genetic polymorphism in the MOLX genes may exist among individuals within a population due to natural allelic variation. As used herein, the terms "gene" and "recombinant gene" refer to nucleic acid molecules comprising an open reading frame (ORF) encoding an MOLX protein, preferably a vertebrate MOLX protein. Such natural allelic variations can typically result in 1-5% variance in the nucleotide sequence ofthe MOLX genes. Any and all such nucleotide variations and resulting amino acid polymorphisms in the MOLX polypeptides, which are the result of natural allelic variation and that do not alter the functional activity of the MOLX polypeptides, are intended to be within the scope ofthe invention.

Moreover, nucleic acid molecules encoding MOLX proteins from other species, and thus that have a nucleotide sequence that differs from the human sequence SEQ ID NOS: l, 3, 5, 7, 9, 1 1, 13, 15, 17, 19, 21, 23, 101, 103, 105, 107, 109, 1 12, 115, 1 17, 1 19, 121, 124, 135, 137, 139, 141, 143, 145, 147, 149, 151, 153, 155, 157, 159, 161, 163, 165, and 166 are intended to be within the scope ofthe invention. Nucleic acid molecules corresponding to natural allelic variants and homologues ofthe MOLX cDNAs ofthe invention can be isolated based on their homology to the human MOLX nucleic acids disclosed herein using the human cDNAs, or a portion thereof, as a hybridization probe according to standard hybridization techniques under stringent hybridization conditions. Accordingly, in another embodiment, an isolated nucleic acid molecule ofthe invention is at least 6 nucleotides in length and hybridizes under stringent conditions to the nucleic acid molecule comprising the nucleotide sequence of SEQ ID NOS:l, 3, 5, 7, 9, 1 1, 13, 15, 17, 19, 21, 23, 101, 103, 105, 107, 109, 1 12, 1 15, 1 17, 1 19, 121, 124, 135, 137, 139, 141, 143, 145, 147, 149, 151, 153, 155, 157, 159, 161, 163, 165, and 166. In another embodiment, the nucleic acid is at least 10, 25, 50, 100, 250, 500, 750, 1000, 1500, or 2000 or more nucleotides in length. In yet another embodiment, an isolated nucleic acid molecule ofthe invention hybridizes to the coding region. As used herein, the term "hybridizes under stringent conditions" is intended to describe conditions for hybridization and washing under which nucleotide sequences at least 60% homologous to each other typically remain hybridized to each other. Homologs (i.e., nucleic acids encoding MOLX proteins derived from species other than human) or other related sequences (e.g., paralogs) can be obtained by low, moderate or high stringency hybridization with all or a portion ofthe particular human sequence as a probe using methods well known in the art for nucleic acid hybridization and cloning.

As used herein, the phrase "stringent hybridization conditions" refers to conditions under which a probe, primer or oligonucleotide will hybridize to its target sequence, but to no other sequences. Stringent conditions are sequence-dependent and will be different in different circumstances. Longer sequences hybridize specifically at higher temperatures than shorter sequences. Generally, stringent conditions are selected to be about 5 °C lower than the thermal melting point (Tm) for the specific sequence at a defined ionic strength and pH. The Tm is the temperature (under defined ionic strength, pH and nucleic acid concentration) at which 50% ofthe probes complementary to the target sequence hybridize to the target sequence at equilibrium. Since the target sequences are generally present at excess, at Tm, 50% ofthe probes are occupied at equilibrium. Typically, stringent conditions will be those in which the salt concentration is less than about 1.0 M sodium ion, typically about 0.01 to 1.0 M sodium ion (or other salts) at pH 7.0 to 8.3 and the temperature is at least about 30°C for short probes, primers or oligonucleotides (e.g., 10 nt to 50 nt) and at least about 60°C for longer probes, primers and oligonucleotides. Stringent conditions may also be achieved with the addition of destabilizing agents, such as formamide. Stringent conditions are known to those skilled in the art and can be found in Ausubel, et al, (eds.), CURRENT PROTOCOLS IN MOLECULAR BIOLOGY, John Wiley & Sons, N.Y. ( 1989), 6.3.1-6.3.6. Preferably, the conditions are such that sequences at least about 65%, 70%, 75%, 85%, 90%, 95%, 98%, or 99% homologous to each other typically remain hybridized to each other. A non-limiting example of stringent hybridization conditions are hybridization in a high salt buffer comprising 6X SSC, 50 mM Tris-HCl (pH 7.5), 1 mM EDTA, 0.02% PVP, 0.02% Ficoll, 0.02% BSA, and 500 mg/ml denatured salmon sperm DNA at 65°C, followed by one or more washes in 0.2X SSC,_.0.01% BSA at 50°C. An isolated nucleic acid molecule ofthe invention that hybridizes under stringent conditions to the sequences of SEQ ID NOS: 1 , 3, 5, 7, 9, 1 1, 13, 15, 17, 19, 21, 23, 101, 103, 105, 107, 109, 1 12, 1 15, 1 17, 1 19, 121, 124, 135, 137, 139, 141, 143, 145, 147, 149, 151, 153, 155, 157, 159, 161, 163, 165, and 166 corresponds to a naturally-occurring nucleic acid molecule. As used herein, a "naturally-occurring" nucleic acid molecule refers to an RNA or DNA molecule having a nucleotide sequence that occurs in nature (e.g., encodes a natural protein).

In a second embodiment, a nucleic acid sequence that is hybridizable to the nucleic acid molecule comprising the nucleotide sequence of SEQ ID NOS: l, 3, 5, 7, 9, 1 1 , 13, 15, 17, 19, 21 , 23, 101, 103, 105, 107, 109, 1 12, 1 15, 1 17, 1 19, 121, 124, 135, 137, 139, 141, 143, 145, 147, 149, 151, 153, 155, 157, 159, 161, 163, 165, and 166 or fragments, analogs or derivatives thereof, under conditions of moderate stringency is provided. A non-limiting example of moderate stringency hybridization conditions are hybridization in 6X SSC, 5X Denhardt's solution, 0.5% SDS and 100 mg/ml denatured salmon sperm DNA at 55°C, followed by one or more washes in IX SSC, 0.1 % SDS at 37°C. Other conditions of moderate stringency that may be used are well-known within the art. See, e.g., Ausubel, et al. (eds.), 1993, CURRENT PROTOCOLS IN MOLECULAR BIOLOGY, John Wiley & Sons, NY, and Kriegler, 1990; GENE TRANSFER AND EXPRESSION, A LABORATORY MANUAL, Stockton Press, NY.

In a third embodiment, a nucleic acid that is hybridizable to the nucleic acid molecule comprising the nucleotide sequences of SEQ ID NOS: l, 3, 5, 7, 9, 1 1, 13, 15, 17, 19, 21, 23, 101, 103, 105, 107, 109, 1 12, 115, 1 17, 1 19, 121, 124, 135, 137, 139, 141, 143,

145, 147, 149, 151, 153, 155, 157, 159, 161, 163, 165, and 166 or fragments, analogs or derivatives thereof, under conditions of low stringency, is provided. A non-limiting example of low stringency hybridization conditions are hybridization in 35% formamide,

5X SSC, 50 mM Tris-HCl (pH 7.5), 5 mM EDTA, 0.02% PVP, 0.02% Ficoll, 0.2% BSA, 100 mg/ml denatured salmon sperm DNA, 10% (wt/vol) dextran sulfate at 40°C, followed by one or more washes in 2X SSC, 25 mM Tris-HCl (pH 7.4), 5 mM EDTA, and 0.1% SDS at 50°C. Other conditions of low stringency that may be used are well known in the art (e.g., as employed for cross-species hybridizations). See, e.g., Ausubel, et al. (eds.), 1993, CURRENT PROTOCOLS IN MOLECULAR BIOLOGY, John Wiley & Sons, NY, and Kriegler, 1990, GENE TRANSFER AND EXPRESSION, A LABORATORY MANUAL, Stockton Press, NY; Shilo and Weinberg, 1981. Proc Natl Acad Sci USA 78: 6789-6792.

Conservative Mutations In addition to naturally-occurring allelic variants of MOLX sequences that may exist in the population, the skilled artisan will further appreciate that changes can be introduced by mutation into the nucleotide sequences of SEQ ID NOS: 1, 3, 5, 7, 9, 1 1, 13, 15, 17, 19, 21, 23, 101, 103, 105, 107, 109, 1 12, 1 15, 1 17, 1 19, 121, 124, 135, 137, 139, 141, 143, 145, 147, 149, 151, 153, 155, 157, 159, 161, 163, 165, and 166 thereby leading to changes in the amino acid sequences ofthe encoded MOLX proteins, without altering the functional ability of said MOLX proteins. For example, nucleotide substitutions leading to amino acid substitutions at "non-essential" amino acid residues can be made in the sequence of SEQ ID NOS:2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 102, 104, 106, 108, 1 1 1 , 114, 1 16, 118, 120, 123, 125, 136, 138, 140, 142, 144, 146, 148, 150, 152, 154, 156, 158, 160, 162, 164, and 167. A "non-essential" amino acid residue is a residue that can be altered from the wild-type sequences ofthe MOLX proteins without altering their biological activity, whereas an "essential" amino acid residue is required for such biological activity. For example, amino acid residues that are conserved among the MOLX proteins ofthe invention are predicted to be particularly non-amenable to alteration. Amino acids for which conservative substitutions can be made are well-known within the art.

Another aspect ofthe invention pertains to nucleic acid molecules encoding MOLX proteins that contain changes in amino acid residues that are not essential for activity. Such MOLX proteins differ in amino acid sequence from SEQ ID NOS:2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 102, 104, 106, 108, 11 1, 1 14, 116, 118, 120, 123, 125, 136,

138, 140, 142, 144, 146, 148, 150, 152, 154, 156, 158, 160, 162, 164, and 167 yet retain biological activity. In one embodiment, the isolated nucleic acid molecule comprises a nucleotide sequence encoding a protein, wherein the protein comprises an amino acid sequence at least about 45%> homologous to the amino acid sequences of SEQ ID NOS:2, 4,6,8, 10, 12, 14, 16, 18,20,22,24, 102, 104, 106, 108, 111, 114, 116, 118, 120, 123, 125, 136, 138, 140, 142, 144, 146, 148, 150, 152, 154, 156, 158, 160, 162, 164, and 167. Preferably, the protein encoded by the nucleic acid molecule is at least about 60% homologous to SEQ IDNOS:2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 102, 104, 106, 108, 111, 114, 116, 118, 120, 123, 125, 136,138, 140, 142, 144, 146, 148, 150, 152, 154, 156, 158, 160, 162, 164, and 167; more preferably at least about 70% homologous to SEQ ID NOS:2, 4, 6, 8, 10, 12, 14, 16, 18,20,22,24, 102, 104, 106, 108, 111, 114, 116, 118, 120, 123, 125, 136, 138, 140, 142, 144, 146, 148, 150, 152, 154, 156, 158, 160, 162, 164, and 167; still more preferably at least about 80% homologous to SEQ ID NOS:2, 4, 6, 8, 10, 12, 14, 16, 18,20,22,24, 102, 104, 106, 108, 111, 114, 116, 118, 120, 123, 125, 136, 138, 140, 142, 144, 146, 148, 150, 152, 154, 156, 158, 160, 162, 164, and 167; even more preferably at least about 90% homologous to SEQ ID NOS:2, 4, 6, 8, 10, 12, 14, 16, 18, 20,22,24, 102, 104, 106, 108, 111, 114, 116, 118, 120, 123, 125, 136, 138, 140, 142, 144, 146, 148, 150, 152, 154, 156, 158, 160, 162, 164, and 167; and most preferably at least about 95% homologous to SEQ ID NOS:2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 102, 104, 106, 108, 111, 114, 116, 118, 120, 123,125, 136, 138, 140, 142, 144, 146, 148, 150, 152, 154, 156, 158, 160, 162, 164, and 167.

An isolated nucleic acid molecule encoding an MOLX protein homologous to the protein of SEQ ID NOS:2, 4, 6, 8, 10, 12, 14, 16, 18,20,22,24, 102, 104, 106, 108, 111, 114, 116, 118, 120, 123, 125, 136, 138, 140, 142, 144, 146, 148, 150, 152, 154, 156, 158, 160, 162, 164, and 167 can be created by introducing one or more nucleotide substitutions, additions or deletions into the nucleotide sequence of SEQ ID NOS:l, 3, 5, 7, 9, 11, 13, 15, 17, 19,21,23, 101, 103, 105, 107, 109, 112, 115, 117, 119, 121, 124, 135, 137, 139, 141,143, 145, 147, 149, 151, 153, 155, 157, 159, 161, 163, 165, and 166 such that one or more amino acid substitutions, additions or deletions are introduced into the encoded protein.

Mutations can be introduced into SEQ ID NOS:2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22,24, 102, 104, 106, 108, 111, 114, 116, 118, 120, 123, 125, 136, 138, 140, 142, 144, 146, 148, 150, 152, 154, 156, 158, 160, 162, 164, and 167 by standard techniques, such as site-directed mutagenesis and PCR-mediated mutagenesis. Preferably, conservative amino acid substitutions are made at one or more predicted, non-essential amino acid residues. A

"conservative amino acid substitution" is one in which the amino acid residue is replaced with an amino acid residue having a similar side chain. Families of amino acid residues having similar side chains have been defined within the art. These families include amino acids with basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine), nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), beta-branched side chains (e.g., threonine, valine, isoleucine) and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine). Thus, a predicted non-essential amino acid residue in the MOLX protein is replaced with another amino acid residue from the same side chain family. Alternatively, in another embodiment, mutations can be introduced randomly along all or part of an MOLX coding sequence, such as by saturation mutagenesis, and the resultant mutants can be screened for MOLX biological activity to identify mutants that retain activity. Following mutagenesis of SEQ ID NOS: l, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 101, 103, 105, 107, 109, 112, 115, 1 17, 119, 121, 124, 135, 137, 139, 141, 143, 145, 147, 149, 151, 153, 155, 157, 159, 161, 163, 165, and 166, the encoded protein can be expressed by any recombinant technology known in the art and the activity ofthe protein can be determ ined .

The relatedness of amino acid families may also be determined based on side chain interactions. Substituted amino acids may be fully conserved "strong" residues or fully conserved "weak" residues. The "strong" group of conserved amino acid residues may be any one ofthe following groups: STA, NEQK, NHQK, NDEQ, QHRK, MILV, MILF, HY, FYW, wherein the single letter amino acid codes are grouped by those amino acids that may be substituted for each other. Likewise, the "weak" group of conserved residues may be any one ofthe following: CSA, ATV, SAG, STNK, STPA, SGND, SNDEQK, NDEQHK, NEQHRK, VLIM, HFY, wherein the letters within each group represent the single letter amino acid code. In one embodiment, a mutant MOLX protein can be assayed for ( ) the ability to form protein: protein interactions with other MOLX proteins, other cell-surface proteins, or biologically-active portions thereof, (ii) complex formation between a mutant MOLX protein and an MOLX ligand; or (iii) the ability of a mutant MOLX protein to bind to an intracellular target protein or biologically-active portion thereof; (e.g. avidin proteins). In yet another embodiment, a mutant MOLX protein can be assayed for the ability to regulate a specific biological function (e.g., regulation of insulin release). Antisense Nucleic Acids

Another aspect ofthe invention pertains to isolated antisense nucleic acid molecules that are hybridizable to or complementary to the nucleic acid molecule comprising the nucleotide sequence of SEQ ID NOS: l, 3, 5, 7, 9, 1 1, 13, 15, 17, 19, 21, 23, 101 , 103, 105, 107, 109, 112, 1 15, 1 17, 119, 121, 124, 135, 137, 139, 141, 143, 145, 147, 149, 151, 153, 155, 157, 159, 161, 163, 165, and 166, or fragments, analogs or derivatives thereof. An "antisense" nucleic acid comprises a nucleotide sequence that is complementary to a "sense" nucleic acid encoding a protein (e.g., complementary to the coding strand of a double-stranded cDNA molecule or complementary to an mRNA sequence). In specific aspects, antisense nucleic acid molecules are provided that comprise a sequence complementary to at least about 10, 25, 50, 100, 250 or 500 nucleotides or an entire MOLX coding strand, or to only a portion thereof. Nucleic acid molecules encoding fragments, homologs, derivatives and analogs of an MOLX protein of SEQ ID NOS:2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 102, 104, 106, 108, 11 1, 1 14, 1 16, 1 18, 120, 123, 125, 136, 138, 140, 142, 144, 146, 148, 150, 152, 154, 156, 158, 160, 162, 164, and 167, or antisense nucleic acids complementary to an MOLX nucleic acid sequence of SEQ ID NOS:l, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 101, 103, 105, 107, 109, 1 12, 1 15, 1 17, 1 19, 121, 124, 135, 137, 139, 141 , 143, 145, 147, 149, 151, 153, 155, 157, 159, 161, 163, 165, and 166, are additionally provided. In one embodiment, an antisense nucleic acid molecule is antisense to a "coding region" ofthe coding strand of a nucleotide sequence encoding an MOLX protein. The term "coding region" refers to the region ofthe nucleotide sequence comprising codons which are translated into amino acid residues. In another embodiment, the antisense nucleic acid molecule is antisense to a "noncoding region" ofthe coding strand of a nucleotide sequence encoding the MOLX protein. The term "noncoding region" refers to 5' and 3' sequences which flank the coding region that are not translated into amino acids (i.e., also referred to as 5' and 3' untranslated regions).

Given the coding strand sequences encoding the MOLX protein disclosed herein, antisense nucleic acids ofthe invention can be designed according to the rules of Watson and Crick or Hoogsteen base pairing. The antisense nucleic acid molecule can be complementary to the entire coding region of MOLX mRNA, but more preferably is an oligonucleotide that is antisense to only a portion ofthe coding or noncoding region of MOLX mRNA. For example, the antisense oligonucleotide can be complementary to the region surrounding the translation start site of MOLX mRNA. An antisense oligonucleotide can be, for example, about 5, 10, 15, 20, 25, 30, 35, 40, 45 or 50 nucleotides in length. An antisense nucleic acid ofthe invention can be constructed using chemical synthesis or enzymatic ligation reactions using procedures known in the art. For example, an antisense nucleic acid (e.g., an antisense oligonucleotide) can be chemically synthesized using naturally-occurring nucleotides or variously modified nucleotides designed to increase the biological stability of the molecules or to increase the physical stability ofthe duplex formed between the antisense and sense nucleic acids (e.g., phosphorothioate derivatives and acridine substituted nucleotides can be used). Examples of modified nucleotides that can be used to generate the antisense nucleic acid include: 5-fluorouracil, 5-bromouracil, 5-chlorouracil, 5-iodouracil, hypoxanthine, xanthine, 4-acetylcytosine, 5-(carboxyhydroxylmethyl) uracil, 5-carboxymethylaminomethyl-2-thiouridine, 5-carboxymethylaminomethyluracil, dihydrouracil, beta-D-galactosylqueosine, inosine, N6-isopentenyladenine, 1 -methylguanine, 1-methylinosine, 2,2-dimethylguanine, 2-methyladenine,

2-methylguanine, 3-methylcytosine, 5-methylcytosine, N6-adenine, 7-methylguanine, 5-methylaminomethyluracil, 5-methoxyaminomethyl-2-thiouracil, beta-D-mannosylqueosine, 5'-methoxycarboxymethyluracil, 5-methoxyuracil, 2-methylthio-N6-isopentenyladenine, uracil-5-oxyacetic acid (v), wybutoxosine, pseudouracil, queosine, 2-thiocytosine, 5-methyl-2-thiouracil, 2-thiouracil, 4-thiouracil, 5-methyluracil, uracil-5-oxyacetic acid methylester, uracil-5-oxyacetic acid (v), 5-methyl-2-thiouracil, 3-(3-amino-3-N-2-carboxypropyl) uracil, (acp3)w, and 2,6-diaminopurine. Alternatively, the antisense nucleic acid can be produced biologically using an expression vector into which a nucleic acid has been subcloned in an antisense orientation (i.e., RNA transcribed from the inserted nucleic acid will be of an antisense orientation to a target nucleic acid of interest, described further in the following subsection).

The antisense nucleic acid molecules ofthe invention are typically administered to a subject or generated in situ such that they hybridize with or bind to cellular mRNA and/or genomic DNA encoding an MOLX protein to thereby inhibit expression of the protein (e.g., by inhibiting transcription and/or translation). The hybridization can be by conventional nucleotide complementarity to form a stable duplex, or, for example, in the case of an antisense nucleic acid molecule that binds to DNA duplexes, through specific interactions in the major groove ofthe double helix. An example of a route of administration of antisense nucleic acid molecules ofthe invention includes direct injection at a tissue site. Alternatively, antisense nucleic acid molecules can be modified to target selected cells and then administered systemically. For example, for systemic administration, antisense molecules can be modified such that they specifically bind to receptors or antigens expressed on a selected cell surface (e.g., by linking the antisense nucleic acid molecules to peptides or antibodies that bind to cell surface receptors or antigens). The antisense nucleic acid molecules can also be delivered to cells using the vectors described herein. To achieve sufficient nucleic acid molecules, vector constructs in which the antisense nucleic acid molecule is placed under the control of a strong pol II or pol III promoter are preferred.

In yet another embodiment, the antisense nucleic acid molecule ofthe invention is an α-anomeric nucleic acid molecule. An α-anomeric nucleic acid molecule forms specific double-stranded hybrids with complementary RNA in which, contrary to the usual β-units, the strands run parallel to each other. See, e.g., Gaultier, et al., 1987. Nucl. Acids Res. 15: 6625-6641. The antisense nucleic acid molecule can also comprise a

2'-o-methylribonucleotide (see, e.g., Inoue, et al. 1987. Nucl. Acids Res. 15: 6131-6148) or a chimeric RNA-DNA analogue (see, e.g., Inoue, et al, 1987. FEES Lett. 215: 327-330.

Ribozymes and PNA Moieties Nucleic acid modifications include, by way of non-limiting example, modified bases, and nucleic acids whose sugar phosphate backbones are modified or derivatized. These modifications are carried out at least in part to enhance the chemical stability ofthe modified nucleic acid, such that they may be used, for example, as antisense binding nucleic acids in therapeutic applications in a subject. In one embodiment, an antisense nucleic acid ofthe invention is a ribozyme.

Ribozymes are catalytic RNA molecules with ribonuclease activity that are capable of cleaving a single-stranded nucleic acid, such as an mRNA, to which they have a complementary region. Thus, ribozymes (e.g., hammerhead ribozymes as described in Haselhoff and Gerlach 1988. Nature 334: 585-591) can be used to catalytically cleave MOLX mRNA transcripts to thereby inhibit translation of MOLX mRNA. A ribozyme having specificity for an MOLX-encoding nucleic acid can be designed based upon the nucleotide sequence of an MOLX cDNA disclosed herein (i.e., SEQ ID NOS:l, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 101, 103, 105, 107, 109, 112, 115, 117, 119, 121, 124, 135, 137, 139, 141, 143, 145, 147, 149, 151, 153, 155, 157, 159, 161, 163, 165, and 166). For example, a derivative of a Tetrahymena L-19 IVS RNA can be constructed in which the nucleotide sequence ofthe active site is complementary to the nucleotide sequence to be cleaved in an MOLX-encoding mRNA. See, e.g., U.S. Patent 4,987,071 to Cech, et al. and U.S. Patent 5,1 16,742 to Cech, et al. MOLX mRNA can also be used to select a catalytic RNA having a specific ribonuclease activity from a pool of RNA molecules. See, e.g., Bartel et α/., (1993) Science 261 : 141 1-1418.

Alternatively, MOLX gene expression can be inhibited by targeting nucleotide sequences complementary to the regulatory region ofthe MOLX nucleic acid (e.g., the MOLX promoter and/or enhancers) to form triple helical structures that prevent transcription of the MOLX gene in target cells. See, e.g., Helene, 1991. Anticancer Drug Des. 6: 569-84; Helene, et al. 1992. Ann. N.Y. Acad. Sci. 660: 27-36; Maher, 1992. Bioassays 14: 807-15.

In various embodiments, the MOLX nucleic acids can be modified at the base moiety, sugar moiety or phosphate backbone to improve, e.g., the stability, hybridization, or solubility ofthe molecule. For example, the deoxyribose phosphate backbone ofthe nucleic acids can be modified to generate peptide nucleic acids. See, e.g., Hyrup, et al, 1996. Bioorg Med Chem 4: 5-23. As used herein, the terms "peptide nucleic acids" or "PNAs" refer to nucleic acid mimics (e.g., DNA mimics) in which the deoxyribose phosphate backbone is replaced by a pseudopeptide backbone and only the four natural nucleobases are retained. The neutral backbone of PNAs has been shown to allow for specific hybridization to DNA and RNA under conditions of low ionic strength. The synthesis of PNA oligomers can be performed using standard solid phase peptide synthesis protocols as described in Hyrup, et al, 1996. supra; Perry-O'Keefe, et al, 1996. Proc. Natl. Acad. Sci. USA 93: 14670-14675.

PNAs of MOLX can be used in therapeutic and diagnostic applications. For example, PNAs can be used as antisense or antigene agents for sequence-specific modulation of gene expression by, e.g., inducing transcription or translation arrest or inhibiting replication. PNAs of MOLX can also be used, for example, in the analysis of single base pair mutations in a gene (e.g., PNA directed PCR clamping; as artificial restriction enzymes when used in combination with other enzymes, e.g., Si nucleases (see, Hyrup, et al, 1996.suprd); or as probes or primers for DNA sequence and hybridization (see, Hyrup, et al, 1996, supra; Perry-O'Keefe, et al, 1996. supra). In another embodiment, PNAs of MOLX can be modified, e.g., to enhance their stability or cellular uptake, by attaching lipophilic or other helper groups to PNA, by the formation of PNA-DNA chimeras, or by the use of liposomes or other techniques of drug delivery known in the art. For example, PNA-DNA chimeras of MOLX can be generated that may combine the advantageous properties of PNA and DNA. Such chimeras allow DNA recognition enzymes (e.g., RNase FI and DNA polymerases) to interact with the DNA portion while the PNA portion would provide high binding affinity and specificity. PNA-DNA chimeras can be linked using linkers of appropriate lengths selected in terms of base stacking, number of bonds between the nucleobases, and orientation (see, Hyrup, et al., 1996. supra). The synthesis of PNA-DNA chimeras can be performed as described in Hyrup, et al, 1996. supra and Finn, et al, 1996. Nucl Acids Res 24: 3357-3363. For example, a DNA chain can be synthesized on a solid support using standard phosphoramidite coupling chemistry, and modified nucleoside analogs, e.g., 5'-(4-methoxytrityl)amino-5'-deoxy-thymidine phosphoramidite, can be used between the PNA and the 5' end of DNA. See, e.g., Mag, et al, 1989. Nucl Acid Res 17: 5973-5988. PNA monomers are then coupled in a stepwise manner to produce a chimeric molecule with a 5' PNA segment and a 3' DNA segment. See, e.g., Finn, et al, 1996. supra. Alternatively, chimeric molecules can be synthesized with a 5' DNA segment and a 3' PNA segment. See, e.g., Petersen, et al, 1975. Bioorg. Pled. Chem. Lett. 5: 1 1 19-1 1 124. In other embodiments, the oligonucleotide may include other appended groups such as peptides (e.g., for targeting host cell receptors in vivo), or agents facilitating transport across the cell membrane (see, e.g., Letsinger, et al, 1989. Proc. Natl. Acad. Sci. U.S.A. 86: 6553-6556; Lemaitre, et al, 1987. Proc. Natl. Acad. Sci. 84: 648-652; PCT Publication No. WO88/09810) or the blood-brain barrier (see, e.g., PCT Publication No. WO 89/10134). In addition, oligonucleotides can be modified with hybridization triggered cleavage agents (see, e.g., Krol, et al, 1988. BioTechniques 6:958-976) or intercalating agents (see, e.g., Zon, 1988. Pharm. Res. 5: 539-549). To this end, the oligonucleotide may be conjugated to another molecule, e.g., a peptide, a hybridization triggered cross-linking agent, a transport agent, a hybridization-triggered cleavage agent, and the like.

MOLX Polypeptides

A polypeptide according to the invention includes a polypeptide including the amino acid sequence of MOLX polypeptides whose sequences are provided in SEQ ID NOS:2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 102, 104, 106, 108, 1 11 , 114, 116, 118, 120, 123, 125, 136, 138, 140, 142, 144, 146, 148, 150, 152, 154, 156, 158, 160, 162, 164, and 167. The invention also includes a mutant or variant protein any of whose residues may be changed from the corresponding residues shown in SEQ ID NOS:2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 102, 104, 106, 108, 11 1, 1 14, 1 16, 1 18, 120, 123, 125, 136, 138, 140, 142, 144, 146, 148, 150, 152, 154, 156, 158, 160, 162, 164, and 167 while still encoding a protein that maintains its MOLX activities and physiological functions, or a functional fragment thereof.

In general, an MOLX variant that preserves MOLX-like function includes any variant in which residues at a particular position in the sequence have been substituted by other amino acids, and further include the possibility of inserting an additional residue or residues between two residues ofthe parent protein as well as the possibility of deleting one or more residues from the parent sequence. Any amino acid substitution, insertion, or deletion is encompassed by the invention. In favorable circumstances, the substitution is a conservative substitution as defined above.

One aspect ofthe invention pertains to isolated MOLX proteins, and biologically- active portions thereof, or derivatives, fragments, analogs or homologs thereof. Also provided are polypeptide fragments suitable for use as immunogens to raise anti-MOLX antibodies. In one embodiment, native MOLX proteins can be isolated from cells or tissue sources by an appropriate purification scheme using standard protein purification techniques. In another embodiment, MOLX proteins are produced by recombinant DNA techniques. Alternative to recombinant expression, an MOLX protein or polypeptide can be synthesized chemically using standard peptide synthesis techniques.

An "isolated" or "purified" polypeptide or protein or biologically-active portion thereof is substantially free of cellular material or other contaminating proteins from the cell or tissue source from which the MOLX protein is derived, or substantially free from chemical precursors or other chemicals when chemically synthesized. The language "substantially free of cellular material" includes preparations of MOLX proteins in which the protein is separated from cellular components ofthe cells from which it is isolated or recombinantly-produced. In one embodiment, the language "substantially free of cellular material" includes preparations of MOLX proteins having less than about 30% (by dry weight) of non-MOLX proteins (also referred to herein as a "contaminating protein"), more preferably less than about 20% of non-MOLX proteins, still more preferably less than about 10% of non-MOLX proteins, and most preferably less than about 5% of non-MOLX proteins. When the MOLX protein or biologically-active portion thereof is recombinantly-produced, it is also preferably substantially free of culture medium, i.e., culture medium represents less than about 20%, more preferably less than about 10%, and most preferably less than about 5% ofthe volume of the MOLX protein preparation. The language "substantially free of chemical precursors or other chemicals" includes preparations of MOLX proteins in which the protein is separated from chemical precursors or other chemicals that are involved in the synthesis ofthe protein. In one embodiment, the language "substantially free of chemical precursors or other chemicals" includes preparations of MOLX proteins having less than about 30% (by dry weight) of chemical precursors or non-MOLX chemicals, more preferably less than about 20% chemical precursors or non-MOLX chemicals, still more preferably less than about 10% chemical precursors or non-MOLX chemicals, and most preferably less than about 5% chemical precursors or non-MOLX chemicals.

Biologically-active portions of MOLX proteins include peptides comprising amino acid sequences sufficiently homologous to or derived from the amino acid sequences of the MOLX proteins (e.g., the amino acid sequence shown in SEQ ID NOS:2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 102, 104, 106, 108, 11 1, 1 14, 1 16, 1 18, 120, 123, 125, 136, 138, 140, 142, 144, 146, 148, 150, 152, 154, 156, 158, 160, 162, 164, and 167) that include fewer amino acids than the full-length MOLX proteins, and exhibit at least one activity of an MOLX protein. Typically, biologically-active portions comprise a domain or motif with at least one activity ofthe MOLX protein. A biologically-active portion of an MOLX protein can be a polypeptide which is, for example, 10, 25, 50, 100 or more amino acid residues in length.

Moreover, other biologically-active portions, in which other regions ofthe protein are deleted, can be prepared by recombinant techniques and evaluated for one or more of the functional activities of a native MOLX protein.

In an embodiment, the MOLX protein has an amino acid sequence shown in SEQ ID NOS:2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 102, 104, 106, 108, 1 1 1 , 1 14, 1 16, 1 18, 120, 123, 125, 136, 138, 140, 142, 144, 146, 148, 150, 152, 154, 156, 158, 160, 162, 164, and 167. In other embodiments, the MOLX protein is substantially homologous to SEQ

ID NOS:2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 102, 104, 106, 108, 11 1 , 1 14, 1 16, 1 18,

120, 123, 125, 136, 138, 140, 142, 144, 146, 148, 150, 152, 154, 156, 158, 160, 162, 164, and 167, and retains the functional activity ofthe protein of SEQ ID NOS:2, 4, 6, 8, 10,

12, 14, 16, 18, 20, 22, 24, 102, 104, 106, 108, 11 1, 114, 116, 118, 120, 123, 125, 136, 138, 140, 142, 144, 146, 148, 150, 152, 154, 156, 158, 160, 162, 164, and 167, yet differs in amino acid sequence due to natural allelic variation or mutagenesis, as described in detail, below. Accordingly, in another embodiment, the MOLX protein is a protein that comprises an amino acid sequence at least about 45% homologous to the amino acid sequence SEQ ID NOS :2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 102, 104, 106, 108, 1 1 1, 1 14, 1 16, 118, 120, 123, 125, 136, 138, 140, 142, 144, 146, 148, 150, 152, 154, 156, 158, 160, 162, 164, and 167, and retains the functional activity ofthe MOLX proteins of SEQ ID NOS:2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 102, 104, 106, 108, 1 11 , 1 14, 116, 1 18, 120, 123, 125, 136, 138, 140, 142, 144, 146, 148, 150, 152, 154, 156, 158, 160, 162, 164, and 167.

Determining Homology Between Two or More Sequences

To determine the percent homology of two amino acid sequences or of two nucleic acids, the sequences are aligned for optimal comparison purposes (e.g., gaps can be introduced in the sequence of a first amino acid or nucleic acid sequence for optimal alignment with a second amino or nucleic acid sequence). The amino acid residues or nucleotides at corresponding amino acid positions or nucleotide positions are then compared. When a position in the first sequence is occupied by the same amino acid residue or nucleotide as the corresponding position in the second sequence, then the molecules are homologous at that position (i.e., as used herein amino acid or nucleic acid "homology" is equivalent to amino acid or nucleic acid "identity").

The nucleic acid sequence homology may be determined as the degree of identity between two sequences. The homology may be determined using computer programs known in the art, such as GAP software provided in the GCG program package. See, Needleman and Wunsch, 1970. J Mol Biol 48: 443-453. Using GCG GAP software with the following settings for nucleic acid sequence comparison: GAP creation penalty of 5.0 and GAP extension penalty of 0.3, the coding region ofthe analogous nucleic acid sequences referred to above exhibits a degree of identity preferably of at least 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99%, with the CDS (encoding) part of the DNA sequence shown in SEQ ID NOS: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 101, 103, 105, 107, 109,

1 12, 115, 1 17, 119, 121, 124, 135, 137, 139, 141, 143, 145, 147, 149, 151, 153, 155, 157,

159, 161, 163, 165, and 166.

The term "sequence identity" refers to the degree to which two polynucleotide or polypeptide sequences are identical on a residue-by-residue basis over a particular region of comparison. The term "percentage of sequence identity" is calculated by comparing two optimally aligned sequences over that region of comparison, determining the number of positions at which the identical nucleic acid base (e.g., A, T, C, G, U, or I, in the case of nucleic acids) occurs in both sequences to yield the number of matched positions, dividing the number of matched positions by the total number of positions in the region of comparison (i.e., the window size), and multiplying the result by 100 to yield the percentage of sequence identity. The term "substantial identity" as used herein denotes a characteristic of a polynucleotide sequence, wherein the polynucleotide comprises a sequence that has at least 80 percent sequence identity, preferably at least 85 percent identity and often 90 to 95 percent sequence identity, more usually at least 99 percent sequence identity as compared to a reference sequence over a comparison region.

Chimeric and Fusion Proteins

The invention also provides MOLX chimeric or fusion proteins. As used herein, an MOLX "chimeric protein" or "fusion protein" comprises an MOLX polypeptide operatively-linked to a non-MOLX polypeptide. An "MOLX polypeptide" refers to a polypeptide having an amino acid sequence corresponding to an MOLX protein (SEQ ID NOS:2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 102, 104, 106, 108, 1 1 1 , 1 14, 1 16, 1 18, 120, 123, 125, 136, 138, 140, 142, 144, 146, 148, 150, 152, 154, 156, 158, 160, 162, 164, and 167), whereas a "non-MOLX polypeptide" refers to a polypeptide having an amino acid sequence corresponding to a protein that is not substantially homologous to the MOLX protein, e.g., a protein that is different from the MOLX protein and that is derived from the same or a different organism. Within an MOLX fusion protein the MOLX polypeptide can correspond to all or a portion of an MOLX protein. In one embodiment, an MOLX fusion protein comprises at least one biologically-active portion of an MOLX protein. In another embodiment, an MOLX fusion protein comprises at least two biologically-active portions of an MOLX protein. In yet another embodiment, an MOLX fusion protein comprises at least three biologically-active portions of an MOLX protein. Within the fusion protein, the term "operatively-linked" is intended to indicate that the MOLX polypeptide and the non-MOLX polypeptide are fused in-frame with one another. The non-MOLX polypeptide can be fused to the N-terminus or C-terminus ofthe MOLX polypeptide.

In one embodiment, the fusion protein is a GST-MOLX fusion protein in which the

MOLX sequences are fused to the C-terminus ofthe GST (glutathione S-transferase) sequences. Such fusion proteins can facilitate the purification of recombinant MOLX polypeptides.

In another embodiment, the fusion protein is an MOLX protein containing a heterologous signal sequence at its N-terminus. In certain host cells (e.g., mammalian host cells), expression and/or secretion of MOLX can be increased through use of a heterologous signal sequence.

In yet another embodiment, the fusion protein is an MOLX-immunoglobulin fusion protein in which the MOLX sequences are fused to sequences derived from a member of the immunoglobulin protein family. The MOLX-immunoglobulin fusion proteins ofthe invention can be incorporated into pharmaceutical compositions and administered to a subject to inhibit an interaction between an MOLX ligand and an MOLX protein on the surface of a cell, to thereby suppress MOLX-mediated signal transduction in vivo. The MOLX-immunoglobulin fusion proteins can be used to affect the bioavailability of an MOLX cognate ligand. Inhibition ofthe MOLX ligand/MOLX interaction may be useful therapeutically for both the treatment of proliferative and differentiative disorders, as well as modulating (e.g. promoting or inhibiting) cell survival. Moreover, the MOLX-immunoglobulin fusion proteins ofthe invention can be used as immunogens to produce anti-MOLX antibodies in a subject, to purify MOLX ligands, and in screening assays to identify molecules that inhibit the interaction of MOLX with an MOLX ligand. An MOLX chimeric or fusion protein ofthe invention can be produced by standard recombinant DNA techniques. For example, DNA fragments coding for the different polypeptide sequences are ligated together in-frame in accordance with conventional techniques, e.g., by employing blunt-ended or stagger-ended termini for ligation, restriction enzyme digestion to provide for appropriate termini, filling-in of cohesive ends as appropriate, alkaline phosphatase treatment to avoid undesirable joining, and enzymatic ligation. In another embodiment, the fusion gene can be synthesized by conventional techniques including automated DNA synthesizers. Alternatively, PCR amplification of gene fragments can be carried out using anchor primers that give rise to complementary overhangs between two consecutive gene fragments that can subsequently be annealed and reamplified to generate a chimeric gene sequence (see, e.g., Ausubel, et al (eds.)

CURRENT PROTOCOLS IN MOLECULAR BIOLOGY, John Wiley & Sons, 1992). Moreover, many expression vectors are commercially available that already encode a fusion moiety

(e.g., a GST polypeptide). An MOLX-encoding nucleic acid can be cloned into such an expression vector such that the fusion moiety is linked in-frame to the MOLX protein. MOLX Agonists and Antagonists

The invention also pertains to variants ofthe MOLX proteins that function as either MOLX agonists (i.e., mimetics) or as MOLX antagonists. Variants ofthe MOLX protein can be generated by mutagenesis (e.g., discrete point mutation or truncation ofthe MOLX protein). An agonist ofthe MOLX protein can retain substantially the same, or a subset of, the biological activities ofthe naturally occurring form ofthe MOLX protein. An antagonist ofthe MOLX protein can inhibit one or more ofthe activities of the naturally occurring form ofthe MOLX protein by, for example, competitively binding to a downstream or upstream member of a cellular signaling cascade which includes the MOLX protein. Thus, specific biological effects can be elicited by treatment with a variant of limited function. In one embodiment, treatment of a subject with a variant having a subset ofthe biological activities ofthe naturally occurring form ofthe protein has fewer side effects in a subject relative to treatment with the naturally occurring form of the MOLX proteins.

Variants ofthe MOLX proteins that function as either MOLX agonists (i.e., mimetics) or as MOLX antagonists can be identified by screening combinatorial libraries of mutants (e.g., truncation mutants) ofthe MOLX proteins for MOLX protein agonist or antagonist activity. In one embodiment, a variegated library of MOLX variants is generated by combinatorial mutagenesis at the nucleic acid level and is encoded by a variegated gene library. A variegated library of MOLX variants can be produced by, for example, enzymatically ligating a mixture of synthetic oligonucleotides into gene sequences such that a degenerate set of potential MOLX sequences is expressible as individual polypeptides, or alternatively, as a set of larger fusion proteins (e.g., for phage display) containing the set of MOLX sequences therein. There are a variety of methods which can be used to produce libraries of potential MOLX variants from a degenerate oligonucleotide sequence. Chemical synthesis of a degenerate gene sequence can be performed in an automatic DNA synthesizer, and the synthetic gene then ligated into an appropriate expression vector. Use of a degenerate set of genes allows for the provision, in one mixture, of all ofthe sequences encoding the desired set of potential MOLX sequences. Methods for synthesizing degenerate oligonucleotides are well-known within the art. See, e.g., Narang, 1983. Tetrahedron 39: 3; Itakura, et al, 1984. Anna. Rev.

Biochem. 53: 323; Itakura, et al, 1984. Science 198: 1056; Ike, et al, 1983. Nucl. Acids

Res. 11 : 477. Polypeptide Libraries

In addition, libraries of fragments ofthe MOLX protein coding sequences can be used to generate a variegated population of MOLX fragments for screening and subsequent selection of variants of an MOLX protein. In one embodiment, a library of coding sequence fragments can be generated by treating a double stranded PCR fragment of an MOLX coding sequence with a nuclease under conditions wherein nicking occurs only about once per molecule, denaturing the double stranded DNA, renaturing the DNA to form double-stranded DNA that can include sense/antisense pairs from different nicked products, removing single stranded portions from reformed duplexes by treatment with Si nuclease, and ligating the resulting fragment library into an expression vector. By this method, expression libraries can be derived which encodes N-terminal and internal fragments of various sizes of the MOLX proteins.

Various techniques are known in the art for screening gene products of combinatorial libraries made by point mutations or truncation, and for screening cDNA libraries for gene products having a selected property. Such techniques are adaptable for rapid screening ofthe gene libraries generated by the combinatorial mutagenesis of MOLX proteins. The most widely used techniques, which are amenable to high throughput analysis, for screening large gene libraries typically include cloning the gene library into replicable expression vectors, transforming appropriate cells with the resulting library of vectors, and expressing the combinatorial genes under conditions in which detection of a desired activity facilitates isolation ofthe vector encoding the gene whose product was detected. Recursive ensemble mutagenesis (REM), a new technique that enhances the frequency of functional mutants in the libraries, can be used in combination with the screening assays to identify MOLX variants. See, e.g., Arkin and Yourvan, 1992. Proc. Natl. Acad. Sci. USA 89: 781 1-7815; Delgrave, et al, 1993. Protein Engineering 6:327-331.

Anti-MOLX Antibodies

The invention encompasses antibodies and antibody fragments, such as F_ab or (F_at,)_2,that bind immunospecifically to any ofthe MOLX polypeptides of said invention. An isolated MOLX protein, or a portion or fragment thereof, can be used as an immunogen to generate antibodies that bind to MOLX polypeptides using standard techniques for polyclonal and monoclonal antibody preparation. The full-length MOLX proteins can be used or, alternatively, the invention provides antigenic peptide fragments of MOLX proteins for use as immunogens. The antigenic MOLX peptides comprises at least 4 amino acid residues ofthe amino acid sequence shown in SEQ ID NOS:2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 102, 104, 106, 108, 1 11, 1 14, 1 16, 1 18, 120, 123, 125, 136, 138, 140, 142, 144, 146, 148, 150, 152, 154, 156, 158, 160, 162, 164, and 167 and encompasses an epitope of MOLX such that an antibody raised against the peptide forms a specific immune complex with MOLX. Preferably, the antigenic peptide comprises at least 6, 8, 10, 15, 20, or 30 amino acid residues. Longer antigenic peptides are sometimes preferable over shorter antigenic peptides, depending on use and according to methods well known to someone skilled in the art.

In certain embodiments ofthe invention, at least one epitope encompassed by the antigenic peptide is a region of MOLX that is located on the surface ofthe protein (e.g., a hydrophilic region). As a means for targeting antibody production, hydropathy plots showing regions of hydrophilicity and hydrophobicity may be generated by any method well known in the art, including, for example, the Kyte Doolittle or the Hopp Woods methods, either with or without Fourier transformation (see, e.g., Hopp and Woods, 1981. Proc. Nat. Acad. Sci. USA 78: 3824-3828; Kyte and Doolittle, 1982. J. Mo Biol. 157: 105-142, each incorporated herein by reference in their entirety).

As disclosed herein, MOLX protein sequences of SEQ ID NOS:2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 102, 104, 106, 108, 1 1 1, 1 14, 116, 1 18, 120, 123, 125, 136, 138, 140, 142, 144, 146, 148, 150, 152, 154, 156, 158, 160, 162, 164, and 167, or derivatives, fragments, analogs or homologs thereof, may be utilized as immunogens in the generation of antibodies that immunospecifically-bind these protein components. The term "antibody" as used herein refers to immunoglobulin molecules and immunologically- active portions of immunoglobulin molecules, i.e., molecules that contain an antigen binding site that specifically-binds (immunoreacts with) an antigen, such as MOLX. Such antibodies include, but are not limited to, polyclonal, monoclonal, chimeric, single chain, F_a and F(_ab_')₂ fragments, and an F_ab expression library. In a specific embodiment, antibodies to human MOLX proteins are disclosed. Various procedures known within the art may be used for the production of polyclonal or monoclonal antibodies to an MOLX protein sequence of SEQ ID NOS:2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 102, 104, 106,

108, 11 1, 1 14, 116, 118, 120, 123, 125, 136, 138, 140, 142, 144, 146, 148, 150, 152, 154,

156, 158, 160, 162, 164, and 167, or a derivative, fragment, analog or homolog thereof.

Some of these proteins are discussed below. For the production of polyclonal antibodies, various suitable host animals (e.g., rabbit, goat, mouse or other mammal) may be immunized by injection with the native protein, or a synthetic variant thereof, or a derivative ofthe foregoing. An appropriate immunogenic preparation can contain, for example, recombinantly-expressed MOLX protein or a chemically-synthesized MOLX polypeptide. The preparation can further include an adjuvant. Various adjuvants used to increase the immunological response include, but are not limited to, Freund's (complete and incomplete), mineral gels (e.g., aluminum hydroxide), surface active substances (e.g., lysolecithin, pluronic polyols, polyanions, peptides, oil emulsions, dinitrophenol, etc.), human adjuvants such as Bacille Calmette-Guerin and Corynebacterium parvum, or similar immunostimulatory agents. If desired, the antibody molecules directed against MOLX can be isolated from the mammal (e.g., from the blood) and further purified by well known techniques, such as protein A chromatography to obtain the IgG fraction.

The term "monoclonal antibody" or "monoclonal antibody composition", as used herein, refers to a population of antibody molecules that contain only one species of an antigen binding site capable of immunoreacting with a particular epitope of MOLX. A monoclonal antibody composition thus typically displays a single binding affinity for a particular MOLX protein with which it immunoreacts. For preparation of monoclonal antibodies directed towards a particular MOLX protein, or derivatives, fragments, analogs or homologs thereof, any technique that provides for the production of antibody molecules by continuous cell line culture may be utilized. Such techniques include, but are not limited to, the hybridoma technique (see, e.g., Kohler & Milstein, 1975. Nature 256: 495-497); the trioma technique; the human B-cell hybridoma technique (see, e.g., Kozbor, et al, 1983. Immunol. Today 4: 72) and the EBV hybridoma technique to produce human monoclonal antibodies (see, e.g., Cole, et al, 1985. In: MONOCLONAL ANTIBODIES AND CANCER THERAPY, Alan R. Liss, Inc., pp. 77-96). Human monoclonal antibodies may be utilized in the practice ofthe invention and may be produced by using human hybridomas (see, e.g., Cote, et al, 1983. Proc Natl Acad Sci USA 80: 2026-2030) or by transforming human B-cells with Epstein Barr Virus in vitro (see, e.g., Cole, et al, 1985. In: MONOCLONAL ANTIBODIES AND CANCER THERAPY, Alan R. Liss, Inc., pp. 77-96). Each of the above citations is incorporated herein by reference in their entirety.

According to the invention, techniques can be adapted for the production of single-chain antibodies specific to an MOLX protein (see, e.g., U.S. Patent No.

4,946,778). In addition, methods can be adapted for the construction of F_ab expression libraries (see, e.g., Huse, et al, 1989. Science 246: 1275-1281) to allow rapid and effective identification of monoclonal F_ab fragments with the desired specificity for an MOLX protein or derivatives, fragments, analogs or homologs thereof. Non-human antibodies can be "humanized" by techniques well known in the art. See, e.g., U.S. Patent No. 5,225,539. Antibody fragments that contain the idiotypes to an MOLX protein may be produced by techniques known in the art including, but not limited to: (i) an F^yp fragment produced by pepsin digestion of an antibody molecule; (ii) an F_ab fragment generated by reducing the disulfide bridges of an F_{ta ')2} fragment; (Hi) an F_ab fragment generated by the treatment of the antibody molecule with papain and a reducing agent; and (iv) F_v fragments.

Additionally, recombinant anti-MOLX antibodies, such as chimeric and humanized monoclonal antibodies, comprising both human and non-human portions, which can be made using standard recombinant DNA techniques, are within the scope of the invention. Such chimeric and humanized monoclonal antibodies can be produced by recombinant DNA techniques known in the art, for example using methods described in International Application No. PCT/US86/02269; European Patent Application No. 184, 187; European Patent Application No. 171,496; European Patent Application No. 173,494; PCT International Publication No. WO 86/01533; U.S. Patent No. 4,816,567; U.S. Pat. No. 5,225,539; European Patent Application No. 125,023; Better, et al, 1988. Science 240: 1041-1043; Liu, et al, 1987. Proc. Natl Acad. Sci. USA 84: 3439-3443; Liu, et al, 1987. J. Immunol. 139: 3521-3526; Sun, et al, 1987. Proc. Natl. Acad. Sci. USA 84: 214-218; Nishimura, et al, 1987. Cancer Res. 47: 999-1005; Wood, et al, 1985. Nature 314 :446-449; Shaw, et al, 1988. J Natl. Cancer Inst. 80: 1553-1559); Morrison(1985) Science 229: 1202-1207; Oi, et al. (1986) BioTechniques 4:214; Jones, et al, 1986. Nature 321 : 552-525; Verhoeyan, et al, 1988. Science 239: 1534; and Beidler, et al, 1988. J. Immunol. 141 : 4053-4060. Each ofthe above citations are incorporated herein by reference in their entirety.

In one embodiment, methods for the screening of antibodies that possess the desired specificity include, but are not limited to, enzyme-linked immunosorbent assay (ELISA) and other immunologically-mediated techniques known within the art. In a specific embodiment, selection of antibodies that are specific to a particular domain of an MOLX protein is facilitated by generation of hybridomas that bind to the fragment of an MOLX protein possessing such a domain. Thus, antibodies that are specific for a desired domain within an MOLX protein, or derivatives, fragments, analogs or homologs thereof, are also provided herein.

Anti-MOLX antibodies may be used in methods known within the art relating to the localization and/or quantitation of an MOLX protein (e.g., for use in measuring levels ofthe MOLX protein within appropriate physiological samples, for use in diagnostic methods, for use in imaging the protein, and the like). In a given embodiment, antibodies for MOLX proteins, or derivatives, fragments, analogs or homologs thereof, that contain the antibody derived binding domain, are utilized as pharmacologically-active compounds (hereinafter "Therapeutics"). An anti-MOLX antibody (e.g., monoclonal antibody) can be used to isolate an

MOLX polypeptide by standard techniques, such as affinity chromatography or immunoprecipitation. An anti-MOLX antibody can facilitate the purification of natural MOLX polypeptide from cells and of recombinantly-produced MOLX polypeptide expressed in host cells. Moreover, an anti-MOLX antibody can be used to detect MOLX protein (e.g., in a cellular lysate or cell supernatant) in order to evaluate the abundance and pattern of expression ofthe MOLX protein. Anti-MOLX antibodies can be used diagnostically to monitor protein levels in tissue as part of a clinical testing procedure, e.g., to, for example, determine the efficacy of a given treatment regimen. Detection can be facilitated by coupling (i.e., physically linking) the antibody to a detectable substance. Examples of detectable substances include various enzymes, prosthetic groups, fluorescent materials, luminescent materials, bioluminescent materials, and radioactive materials. Examples of suitable enzymes include horseradish peroxidase, alkaline phosphatase, β-galactosidase, or acetylcholinesterase; examples of suitable prosthetic group complexes include streptavidin/biotin and avidin/biotin; examples of suitable fluorescent materials include umbelliferone, fluorescein, fluorescein isothiocyanate, rhodamine, dichlorotriazinylamine fluorescein, dansyl chloride or phycoerythrin; an example of a luminescent material includes luminol; examples of bioluminescent materials include luciferase, luciferin, and aequorin, and examples of suitable radioactive material include

MOLX Recombinant Expression Vectors and Host Cells

Another aspect ofthe invention pertains to vectors, preferably expression vectors, containing a nucleic acid encoding an MOLX protein, or derivatives, fragments, analogs or homologs thereof. As used herein, the term "vector" refers to a nucleic acid molecule capable of transporting another nucleic acid to which it has been linked. One type of vector is a "plasmid", which refers to a circular double stranded DNA loop into which additional DNA segments can be ligated. Another type of vector is a viral vector, wherein additional DNA segments can be ligated into the viral genome. Certain vectors are capable of autonomous replication in a host cell into which they are introduced (e.g., bacterial vectors having a bacterial origin of replication and episomal mammalian vectors). Other vectors (e.g., non-episomal mammalian vectors) are integrated into the genome of a host cell upon introduction into the host cell, and thereby are replicated along with the host genome. Moreover, certain vectors are capable of directing the expression of genes to which they are operatively-linked. Such vectors are referred to herein as "expression vectors". In general, expression vectors of utility in recombinant DNA techniques are often in the form of plasmids. In the present specification, "plasmid" and "vector" can be used interchangeably as the plasmid is the most commonly used form of vector. However, the invention is intended to include such other forms of expression vectors, such as viral vectors (e.g., replication defective retroviruses, adenoviruses and adeno-associated viruses), which serve equivalent functions.

The recombinant expression vectors of the invention comprise a nucleic acid ofthe invention in a form suitable for expression of the nucleic acid in a host cell, which means that the recombinant expression vectors include one or more regulatory sequences, selected on the basis ofthe host cells to be used for expression, that is operatively-linked to the nucleic acid sequence to be expressed. Within a recombinant expression vector, "operably-linked" is intended to mean that the nucleotide sequence of interest is linked to the regulatory sequence(s) in a manner that allows for expression of the nucleotide sequence (e.g., in an in vitro transcription/translation system or in a host cell when the vector is introduced into the host cell).

The term "regulatory sequence" is intended to includes promoters, enhancers and other expression control elements (e.g., polyadenylation signals). Such regulatory sequences are described, for example, in Goeddel, GENE EXPRESSION TECHNOLOGY: METHODS IN ENZYMOLOGY 185, Academic Press, San Diego, Calif. (1990). Regulatory sequences include those that direct constitutive expression of a nucleotide sequence in many types of host cell and those that direct expression ofthe nucleotide sequence only in certain host cells (e.g., tissue-specific regulatory sequences). It will be appreciated by those skilled in the art that the design ofthe expression vector can depend on such factors as the choice ofthe host cell to be transformed, the level of expression of protein desired, etc. The expression vectors ofthe invention can be introduced into host cells to thereby produce proteins or peptides, including fusion proteins or peptides, encoded by nucleic acids as described herein (e.g., MOLX proteins, mutant forms of MOLX proteins, fusion proteins, etc.).

The recombinant expression vectors of the invention can be designed for expression of MOLX proteins in prokaryotic or eukaryotic cells. For example, MOLX proteins can be expressed in bacterial cells such as Escherichia coli, insect cells (using baculovirus expression vectors) yeast cells or mammalian cells. Suitable host cells are discussed further in Goeddel, GENE EXPRESSION TECHNOLOGY: METHODS IN

ENZYMOLOGY 185, Academic Press, San Diego, Calif. (1990). Alternatively, the recombinant expression vector can be transcribed and translated in vitro, for example using T7 promoter regulatory sequences and T7 polymerase.

Expression of proteins in prokaryotes is most often carried out in Escherichia coli with vectors containing constitutive or inducible promoters directing the expression of either fusion or non-fusion proteins. Fusion vectors add a number of amino acids to a protein encoded therein, usually to the amino terminus ofthe recombinant protein. Such fusion vectors typically serve three purposes: (i) to increase expression of recombinant protein; (ii) to increase the solubility ofthe recombinant protein; and (iii) to aid in the purification ofthe recombinant protein by acting as a ligand in affinity purification.

Often, in fusion expression vectors, a proteolytic cleavage site is introduced at the junction ofthe fusion moiety and the recombinant protein to enable separation ofthe recombinant protein from the fusion moiety subsequent to purification ofthe fusion protein. Such enzymes, and their cognate recognition sequences, include Factor Xa, thrombin and enterokinase. Typical fusion expression vectors include pGEX (Pharmacia Biotech Inc; Smith and Johnson, 1988. Gene 67: 31-40), pMAL (New England Biolabs, Beverly, Mass.) and pRIT5 (Pharmacia, Piscataway, NJ.) that fuse glutathione S-transferase (GST), maltose E binding protein, or protein A, respectively, to the target recombinant protein. Examples of suitable inducible non-fusion E. coli expression vectors include pTrc

(Amrann et al, (1988) Gene 69:301-315) and pET l id (Studier et al, GENE EXPRESSION TECHNOLOGY: METHODS IN ENZYMOLOGY 185, Academic Press, San Diego, Calif. (1990) 60-89). One strategy to maximize recombinant protein expression in E. coli is to express the protein in a host bacteria with an impaired capacity to proteolytically cleave the recombinant protein. See, e.g., Gottesman, GENE EXPRESSION TECHNOLOGY: METHODS IN ENZYMOLOGY 185, Academic Press, San Diego, Calif. (1990) 1 19-128. Another strategy is to alter the nucleic acid sequence ofthe nucleic acid to be inserted into an expression vector so that the individual codons for each amino acid are those preferentially utilized in E. coli (see, e.g., Wada, et al, 1992. Nucl. Acids Res. 20: 211 1-2118). Such alteration of nucleic acid sequences ofthe invention can be carried out by standard DNA synthesis techniques. In another embodiment, the MOLX expression vector is a yeast expression vector.

Examples of vectors for expression in yeast Saccharomyces cerivisae include pYepSecl (Baldari, et al, 1987. EMBO J. 6: 229-234), pMFa (Kurjan and Herskowitz, 1982. Cell 30: 933-943), pJRY88 (Schultz et al, 1987. Gene 54: 1 13-123), pYES2 (Invitrogen Corporation, San Diego, Calif), and picZ (InVitrogen Corp, San Diego, Calif). Alternatively, MOLX can be expressed in insect cells using baculovirus expression vectors. Baculovirus vectors available for expression of proteins in cultured insect cells (e.g., SF9 cells) include the pAc series (Smith, et al, 1983. Mol Cell. Biol. 3: 2156-2165) and the pVL series (Lucklow and Summers, 1989. Virology 170: 31-39).

In yet another embodiment, a nucleic acid ofthe invention is expressed in mammalian cells using a mammalian expression vector. Examples of mammalian expression vectors include pCDM8 (Seed, 1987. Nature 329: 840) and pMT2PC (Kaufman, et al, 1987. EMBO J. 6: 187-195). When used in mammalian cells, the expression vector's control functions are often provided by viral regulatory elements. For example, commonly used promoters are derived from polyoma, adenovirus 2, cytomegalovirus, and simian virus 40. For other suitable expression systems for both ^'prokaryotic and eukaryotic cells see, e.g., Chapters 16 and 17 of Sambrook, et al, MOLECULAR CLONING: A LABORATORY MANUAL. 2nd ed., Cold Spring Harbor Laboratory, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1989.

In another embodiment, the recombinant mammalian expression vector is capable of directing expression ofthe nucleic acid preferentially in a particular cell type (e.g., tissue-specific regulatory elements are used to express the nucleic acid). Tissue-specific regulatory elements are known in the art. Non-limiting examples of suitable tissue-specific promoters include the albumin promoter (liver-specific; Pinkert, et al,

1987. Genes Dev. 1: 268-277), lymphoid-specific promoters (Calame and Eaton, 1988. Adv. Immunol. 43: 235-275), in particular promoters of T cell receptors (Winoto and Baltimore, 1989. EMBO J. 8: 729-733) and immunoglobulins (Banerji, et al, 1983. Cell 33: 729-740; Queen and Baltimore, 1983. Cell 33: 741-748), neuron-specific promoters (e.g., the neurofilament promoter; Byrne and Ruddle, 1989. Proc. Nat Acad. Sci. USA 86: 5473-5477), pancreas-specific promoters (Edlund, et al, 1985. Science 230: 912-916), and mammary gland-specific promoters (e.g., milk whey promoter; U.S. Pat. No. 4,873,316 and European Application Publication No. 264, 166). Developmentally-regulated promoters are also encompassed, e.g., the murine hox promoters (Kessel and Grass, 1990. Science 249: 374-379) and the α-fetoprotein promoter (Campes and Tilghman, 1989. Genes Dev. 3: 537-546).

The invention further provides a recombinant expression vector comprising a DNA molecule ofthe invention cloned into the expression vector in an antisense orientation. That is, the DNA molecule is operatively-linked to a regulatory sequence in a manner that allows for expression (by transcription ofthe DNA molecule) of an RNA molecule that is antisense to MOLX mRNA. Regulatory sequences operatively linked to a nucleic acid cloned in the antisense orientation can be chosen that direct the continuous expression of the antisense RNA molecule in a variety of cell types, for instance viral promoters and/or enhancers, or regulatory sequences can be chosen that direct constitutive, tissue specific or cell type specific expression of antisense RNA. The antisense expression vector can be in the form of a recombinant plasmid, phagemid or attenuated virus in which antisense nucleic acids are produced under the control of a high efficiency regulatory region, the activity of which can be determined by the cell type into which the vector is introduced. For a discussion ofthe regulation of gene expression using antisense genes see, e.g., Weintraub, et al, "Antisense RNA as a molecular tool for genetic analysis," Reviews- Trends in Genetics, Vol. 1(1) 1986.

Another aspect ofthe invention pertains to host cells into which a recombinant expression vector ofthe invention has been introduced. The terms "host cell" and "recombinant host cell" are used interchangeably herein. It is understood that such terms refer not only to the particular subject cell but also to the progeny or potential progeny of such a cell. Because certain modifications may occur in succeeding generations due to either mutation or environmental influences, such progeny may not, in fact, be identical to the parent cell, but are still included within the scope ofthe term as used herein. A host cell can be any prokaryotic or eukaryotic cell. For example, MOLX protein can be expressed in bacterial cells such as E. coli, insect cells, yeast or mammalian cells (such as Chinese hamster ovary cells (CHO) or COS cells). Other suitable host cells are known to those skilled in the art. Vector DNA can be introduced into prokaryotic or eukaryotic cells via conventional transformation or transfection techniques. As used herein, the terms "transformation" and "transfection" are intended to refer to a variety of art-recognized techniques for introducing foreign nucleic acid (e.g., DNA) into a host cell, including calcium phosphate or calcium chloride co-precipitation, DEAE-dextran-mediated transfection, lipofection, or electroporation. Suitable methods for transforming or transfecting host cells can be found in Sambrook, et al. (MOLECULAR CLONING: A LABORATORY MANUAL. 2nd ed., Cold Spring Harbor Laboratory, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1989), and other laboratory manuals.

For stable transfection of mammalian cells, it is known that, depending upon the expression vector and transfection technique used, only a small fraction of cells may integrate the foreign DNA into their genome. In order to identify and select these integrants, a gene that encodes a selectable marker (e.g., resistance to antibiotics) is generally introduced into the host cells along with the gene of interest. Various selectable markers include those that confer resistance to drugs, such as G418, hygromycin and methotrexate. Nucleic acid encoding a selectable marker can be introduced into a host cell on the same vector as that encoding MOLX or can be introduced on a separate vector. Cells stably transfected with the introduced nucleic acid can be identified by drug selection (e.g., cells that have incorporated the selectable marker gene will survive, while the other cells die). A host cell ofthe invention, such as a prokaryotic or eukaryotic host cell in culture, can be used to produce (i.e., express) MOLX protein. Accordingly, the invention further provides methods for producing MOLX protein using the host cells ofthe invention. In one embodiment, the method comprises culturing the host cell of invention (into which a recombinant expression vector encoding MOLX protein has been introduced) in a suitable medium such that MOLX protein is produced. In another embodiment, the method further comprises isolating MOLX protein from the medium or the host cell. Transgenic MOLX Animals

The host cells of the invention can also be used to produce non-human transgenic animals. For example, in one embodiment, a host cell ofthe invention is a fertilized oocyte or an embryonic stem cell into which MOLX protein-coding sequences have been introduced. Such host cells can then be used to create non-human transgenic animals in which exogenous MOLX sequences have been introduced into their genome or homologous recombinant animals in which endogenous MOLX sequences have been altered. Such animals are useful for studying the function and/or activity of MOLX protein and for identifying and/or evaluating modulators of MOLX protein activity. As used herein, a "transgenic animal" is a non-human animal, preferably a mammal, more preferably a rodent such as a rat or mouse, in which one or more ofthe cells ofthe animal includes a transgene. Other examples of transgenic animals include non-human primates, sheep, dogs, cows, goats, chickens, amphibians, etc. A transgene is exogenous DNA that is integrated into the genome of a cell from which a transgenic animal develops and that remains in the genome ofthe mature animal, thereby directing the expression of an encoded gene product in one or more cell types or tissues ofthe transgenic animal. As used herein, a "homologous recombinant animal" is a non-human animal, preferably a mammal, more preferably a mouse, in which an endogenous MOLX gene has been altered by homologous recombination between the endogenous gene and an exogenous DNA molecule introduced into a cell ofthe animal, e.g., an embryonic cell ofthe animal, prior to development ofthe animal.

A transgenic animal ofthe invention can be created by introducing MOLX-encoding nucleic acid into the male pronuclei of a fertilized oocyte (e.g., by microinjection, retroviral infection) and allowing the oocyte to develop in a pseudopregnant female foster animal. The human MOLX cDNA sequences of SEQ ID NOS: l , 3, 5, 7, 9, 1 1, 13, 15, 17, 19, 21, 23, 101, 103, 105, 107, 109, 1 12, 115, 117, 1 19, 121, 124, 135, 137, 139, 141, 143, 145, 147, 149, 151, 153, 155, 157, 159, 161, 163, 165, and 166 can be introduced as a transgene into the genome of a non-human animal. Alternatively, a non-human homologue ofthe human MOLX gene, such as a mouse MOLX gene, can be isolated based on hybridization to the human MOLX cDNA

(described further supra) and used as a transgene. Intronic sequences and polyadenylation signals can also be included in the transgene to increase the efficiency of expression of the transgene. A tissue-specific regulatory sequence(s) can be operably-linked to the MOLX transgene to direct expression of MOLX protein to particular cells. Methods for generating transgenic animals via embryo manipulation and microinjection, particularly animals such as mice, have become conventional in the art and are described, for example, in U.S. Patent Nos. 4,736,866; 4,870,009; and 4,873,191 ; and Hogan, 1986. In: MANIPULATING THE MOUSE EMBRYO, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. Similar methods are used for production of other transgenic animals. A transgenic founder animal can be identified based upon the presence ofthe MOLX transgene in its genome and/or expression of MOLX mRNA in tissues or cells ofthe animals. A transgenic founder animal can then be used to breed additional animals carrying the transgene. Moreover, transgenic animals carrying a transgene-encoding

MOLX protein can further be bred to other transgenic animals carrying other transgenes. To create a homologous recombinant animal, a vector is prepared which contains at least a portion of an MOLX gene into which a deletion, addition or substitution has been introduced to thereby alter, e.g., functionally disrupt, the MOLX gene. The MOLX gene can be a human gene (e.g., the cDNA of SEQ ID NOS: 1 , 3, 5, 7, 9, 11, 13, 15, 17, 19, 21 , 23, 101, 103, 105, 107, 109, 1 12, 1 15, 1 17, 1 19, 121 , 124, 135, 137, 139, 141, 143, 145, 147, 149, 151, 153, 155, 157, 159, 161, 163, 165, and 166), but more preferably, is a non-human homologue of a human MOLX gene. For example, a mouse homologue of human MOLX gene of SEQ ID NOS: 1, 3, 5, 7, 9, 1 1, 13, 15, 17, 19, 21, 23, 101, 103, 105, 107, 109, 112, 1 15, 117, 1 19, 121, 124, 135, 137, 139, 141 , 143, 145, 147, 149, 151, 153, 155, 157, 159, 161, 163, 165, and 166 can be used to construct a homologous recombination vector suitable for altering an endogenous MOLX gene in the mouse genome. In one embodiment, the vector is designed such that, upon homologous recombination, the endogenous MOLX gene is functionally disrupted (i.e., no longer encodes a functional protein; also referred to as a "knock out" vector).

Alternatively, the vector can be designed such that, upon homologous recombination, the endogenous MOLX gene is mutated or otherwise altered but still encodes functional protein (e.g., the upstream regulatory region can be altered to thereby alter the expression ofthe endogenous MOLX protein). In the homologous recombination vector, the altered portion ofthe MOLX gene is flanked at its 5'- and 3 '-termini by additional nucleic acid ofthe MOLX gene to allow for homologous recombination to occur between the exogenous MOLX gene carried by the vector and an endogenous

MOLX gene in an embryonic stem cell. The additional flanking MOLX nucleic acid is of sufficient length for successful homologous recombination with the endogenous gene. Typically, several kilobases of flanking DNA (both at the 5'- and 3'-termini) are included in the vector. See, e.g., Thomas, et al, 1987. Cell 51 : 503 for a description of homologous recombination vectors. The vector is ten introduced into an embryonic stem cell line (e.g., by electroporation) and cells in which the introduced MOLX gene has homologously- recombined with the endogenous MOLX gene are selected. See, e.g., Li, et al, 1992. Cell 69: 915.

The selected cells are then injected into a blastocyst of an animal (e.g., a mouse) to form aggregation chimeras. See, e.g., Bradley, 1987. In: TERATOCARCINOMAS AND EMBRYONIC STEM CELLS: A PRACTICAL APPROACH, Robertson, ed. IRL, Oxford, pp. 1 13-152. A chimeric embryo can then be implanted into a suitable pseudopregnant female foster animal and the embryo brought to term. Progeny harboring the homologously- recombined DNA in their germ cells can be used to breed animals in which all cells ofthe animal contain the homologously-recombined DNA by germline transmission ofthe transgene. Methods for constructing homologous recombination vectors and homologous recombinant animals are described further in Bradley, 1991. Curr. Opin. Biotechnol 2:

823-829; PCT International Publication Nos.: WO 90/1 1354; WO 91/01 140; WO 92/0968; and WO 93/04169.

In another embodiment, transgenic non-humans animals can be produced that contain selected systems that allow for regulated expression ofthe transgene. One example of such a system is the cre/loxP recombinase system of bacteriophage PL For a description ofthe cre/loxP recombinase system, See, e.g., Lakso, et al, 1992. Proc. Natl Acad. Sci. USA 89: 6232-6236. Another example of a recombinase system is the FLP recombinase system of Saccharomyces cerevisiae. See, O'Gorman, et al, 1991. Science 251 :1351 -1355. If a cre/loxP recombinase system is used to regulate expression ofthe transgene, animals containing transgenes encoding both the Cre recombinase and a selected protein are required. Such animals can be provided through the construction of "double" transgenic animals, e.g., by mating two transgenic animals, one containing a transgene encoding a selected protein and the other containing a transgene encoding a recombinase. Clones ofthe non-human transgenic animals described herein can also be produced according to the methods described in Wilmut, et al, 1997. Nature 385: 810-813. In brief, a cell (e.g., a somatic cell) from the transgenic animal can be isolated and induced to exit the growth cycle and enter G₀ phase. The quiescent cell can then be fused, e.g., through the use of electrical pulses, to an enucleated oocyte from an animal ofthe same species from which the quiescent cell is isolated. The reconstructed oocyte is then cultured such that it develops to morula or blastocyte and then transferred to pseudopregnant female foster animal. The offspring borne of this female foster animal will be a clone ofthe animal from which the cell (e.g., the somatic cell) is isolated.

Pharmaceutical Compositions

The MOLX nucleic acid molecules, MOLX proteins, and anti-MOLX antibodies (also referred to herein as "active compounds") ofthe invention, and derivatives, fragments, analogs and homologs thereof, can be incorporated into pharmaceutical compositions suitable for administration. Such compositions typically comprise the nucleic acid molecule, protein, or antibody and a pharmaceutically acceptable carrier. As used herein, "pharmaceutically acceptable carrier" is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration. Suitable carriers are described in the most recent edition of Remington's Pharmaceutical Sciences, a standard reference text in the field, which is incorporated herein by reference. Preferred examples of such carriers or diluents include, but are not limited to, water, saline, finger's solutions, dextrose solution, and 5% human serum albumin. Liposomes and non-aqueous vehicles such as fixed oils may also be used. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active compound, use thereof in the compositions is contemplated. Supplementary active compounds can also be incorporated into the compositions.

A pharmaceutical composition ofthe invention is formulated to be compatible with its intended route of administration. Examples of routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., inhalation), transdermal (i.e., topical), transmucosal, and rectal administration. Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid (EDTA); buffers such as acetates, citrates or phosphates, and agents for the adjustment of tonicity such as sodium chloride or dextrose. The pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.

Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL^™ (BASF, Parsippany, NJ.) or phosphate buffered saline (PBS). In all cases, the composition must be sterile and should be fluid to the extent that easy syringeability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance ofthe required particle size in the case of dispersion and by the use of surfactants. Prevention ofthe action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as manitol, sorbitol, sodium chloride in the composition. Prolonged absorption ofthe injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin.

Sterile injectable solutions can be prepared by incorporating the active compound (e.g., an MOLX protein or anti-MOLX antibody) in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, methods of preparation are vacuum drying and freeze-drying that yields a powder ofthe active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.

Oral compositions generally include an inert diluent or an edible carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed. Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part ofthe composition. The tablets, pills, capsules, troches and the like can contain any ofthe following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.

For administration by inhalation, the compounds are delivered in the form of an aerosol spray from pressured container or dispenser which contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer.

Systemic administration can also be by transmucosal or transdermal means. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives. Transmucosal administration can be accomplished through the use of nasal sprays or suppositories. For transdermal administration, the active compounds are formulated into ointments, salves, gels, or creams as generally known in the art.

The compounds can also be prepared in the form of suppositories (e.g., with conventional suppository bases such as cocoa butter and other glycerides) or retention enemas for rectal delivery. In one embodiment, the active compounds are prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art. The materials can also be obtained commercially from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies to viral antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Patent No. 4,522,811.

It is especially advantageous to formulate oral or parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms ofthe invention are dictated by and directly dependent on the unique characteristics ofthe active compound and the particular therapeutic effect to be achieved, and the limitations inherent in the art of compounding such an active compound for the treatment of individuals.

The nucleic acid molecules ofthe invention can be inserted into vectors and used as gene therapy vectors. Gene therapy vectors can be delivered to a subject by, for example, intravenous injection, local administration (see, e.g., U.S. Patent No. 5,328,470) or by stereotactic injection (see, e.g., Chen, et al, 1994. Proc. Natl. Acad. Sci. USA 91 : 3054-3057). The pharmaceutical preparation ofthe gene therapy vector can include the gene therapy vector in an acceptable diluent, or can comprise a slow release matrix in which the gene delivery vehicle is imbedded. Alternatively, where the complete gene delivery vector can be produced intact from recombinant cells, e.g., retroviral vectors, the pharmaceutical preparation can include one or more cells that produce the gene delivery system.

The pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.

Screening and Detection Methods The isolated nucleic acid molecules ofthe invention can be used to express MOLX protein (e.g., via a recombinant expression vector in a host cell in gene therapy applications), to detect MOLX mRNA (e.g., in a biological sample) or a genetic lesion in an MOLX gene, and to modulate MOLX activity, as described further, below. In addition, the MOLX proteins can be used to screen drugs or compounds that modulate the MOLX protein activity or expression as well as to treat disorders characterized by insufficient or excessive production of MOLX protein or production of MOLX protein forms that have decreased or aberrant activity compared to MOLX wild-type protein (e.g.; diabetes (regulates insulin release); obesity (binds and transport lipids); metabolic disturbances associated with obesity, the metabolic syndrome X as well as anorexia and wasting disorders associated with chronic diseases and various cancers, and infectious disease(possesses anti-microbial activity) and the various dyslipidemias. In addition, the anti-MOLX antibodies ofthe invention can be used to detect and isolate MOLX proteins and modulate MOLX activity. In yet a further aspect, the invention can be used in methods to influence appetite, absorption of nutrients and the disposition of metabolic substrates in both a positive and negative fashion.

The invention further pertains to novel agents identified by the screening assays described herein and uses thereof for treatments as described, supra.

Screening Assays

The invention provides a method (also referred to herein as a "screening assay") for identifying modulators, i.e., candidate or test compounds or agents (e.g., peptides, peptidomimetics, small molecules or other drugs) that bind to MOLX proteins or have a stimulatory or inhibitory effect on, e.g., MOLX protein expression or MOLX protein activity. The invention also includes compounds identified in the screening assays described herein.

In one embodiment, the invention provides assays for screening candidate or test compounds which bind to or modulate the activity ofthe membrane-bound form of an MOLX protein or polypeptide or biologically-active portion thereof. The test compounds ofthe invention can be obtained using any of the numerous approaches in combinatorial library methods known in the art, including: biological libraries; spatially addressable parallel solid phase or solution phase libraries; synthetic library methods requiring deconvolution; the "one-bead one-compound" library method; and synthetic library methods using affinity chromatography selection. The biological library approach is limited to peptide libraries, while the other four approaches are applicable to peptide, non-peptide oligomer or small molecule libraries of compounds. See, e.g., Lam, 1997. Anticancer Drug Design 12: 145.

A "small molecule" as used herein, is meant to refer to a composition that has a molecular weight of less than about 5 kD and most preferably less than about 4 kD. Small molecules can be, e.g., nucleic acids, peptides, polypeptides, peptidomimetics, carbohydrates, lipids or other organic or inorganic molecules. Libraries of chemical and/or biological mixtures, such as fungal, bacterial, or algal extracts, are known in the art and can be screened with any ofthe assays ofthe invention. Examples of methods for the synthesis of molecular libraries can be found in the art, for example in: DeWitt, et al, 1993. Proc. Natl. Acad. Sci. USA. 90: 6909; Erb, et al, 1994. Proc. Natl Acad. Sci. U.S.A. 91 : 11422; Zuckermann, et al, 1994. J. Med. Chem. 37: 2678; Cho, et al, 1993. Science 261 : 1303; Carrell, et al, 1994. Angew. Chem. Int. Ed. Engl. 33: 2059; Carell, et al, 1994. Angew. Chem. Int. Ed. Engl. 33: 2061 ; and Gallop, et al, 1994. J. Med. Chem. 37: 1233.

Libraries of compounds may be presented in solution (e.g., Houghten, 1992. Biotechniques 13: 412-421), or on beads (Lam, 1991. Nature 354: 82-84), on chips (Fodor, 1993. Nature 364: 555-556), bacteria (Ladner, U.S. Patent No. 5,223,409), spores (Ladner, U.S. Patent 5,233,409), plasmids (Cull, et al, 1992. Proc. Natl. Acad. Sci. USA 89: 1865-1869) or on phage (Scott and Smith, 1990. Sc/^'e7?ce 249: 386-390; Devlin, 1990. Science 249: 404-406; Cwirla, et al, 1990. Proc. Natl. Acad. Sci. U.S.A. 87: 6378-6382; Felici, 1991. J. Mol. Biol. 222: 301-310; Ladner, U.S. Patent No. 5,233,409.).

In one embodiment, an assay is a cell-based assay in which a cell which expresses a membrane-bound form of MOLX protein, or a biologically-active portion thereof, on the cell surface is contacted with a test compound and the ability of the test compound to bind to an MOLX protein determined. The cell, for example, can of mammalian origin or a yeast cell. Determining the ability ofthe test compound to bind to the MOLX protein can be accomplished, for example, by coupling the test compound with a radioisotope or enzymatic label such that binding ofthe test compound to the MOLX protein or biologically-active portion thereof can be determined by detecting the labeled compound in a complex. For example, test compounds can be labeled with ^{, 25}I, ^j3S, ^l4C, or Η, either directly or indirectly, and the radioisotope detected by direct counting of radioemission or by scintillation counting. Alternatively, test compounds can be enzymatically-labeled with, for example, horseradish peroxidase, alkaline phosphatase, or luciferase, and the enzymatic label detected by determination of conversion of an appropriate substrate to product. In one embodiment, the assay comprises contacting a cell which expresses a membrane-bound form of MOLX protein, or a biologically-active portion thereof, on the cell surface with a known compound which binds MOLX to form an assay mixture, contacting the assay mixture with a test compound, and determining the ability of the test compound to interact with an MOLX protein, wherein determining the ability ofthe test compound to interact with an MOLX protein comprises determining the ability ofthe test compound to preferentially bind to MOLX protein or a biologically-active portion thereof as compared to the known compound. In another embodiment, an assay is a cell-based assay comprising contacting a cell expressing a membrane-bound form of MOLX protein, or a biologically-active portion thereof, on the cell surface with a test compound and determining the ability ofthe test compound to modulate (e.g., stimulate or inhibit) the activity ofthe MOLX protein or biologically-active portion thereof. Determining the ability ofthe test compound to modulate the activity of MOLX or a biologically-active portion thereof can be accomplished, for example, by determining the ability ofthe MOLX protein to bind to or interact with an MOLX target molecule. As used herein, a "target molecule" is a molecule with which an MOLX protein binds or interacts in nature, for example, a molecule on the surface of a cell which expresses an MOLX interacting protein, a molecule on the surface of a second cell, a molecule in the extracellular milieu, a molecule associated with the internal surface of a cell membrane or a cytoplasmic molecule. An MOLX target molecule can be a non-MOLX molecule or an MOLX protein or polypeptide ofthe invention. In one embodiment, an MOLX target molecule is a component of a signal transduction pathway that facilitates transduction of an extracellular signal (e.g. a signal generated by binding of a compound to a membrane-bound MOLX molecule) through the cell membrane and into the cell. The target, for example, can be a second intercellular protein that has catalytic activity or a protein that facilitates the association of downstream signaling molecules with MOLX. Determining the ability ofthe MOLX protein to bind to or interact with an MOLX target molecule can be accomplished by one ofthe methods described above for determining direct binding. In one embodiment, determining the ability ofthe MOLX protein to bind to or interact with an MOLX target molecule can be accomplished by determining the activity ofthe target molecule. For example, the activity ofthe target molecule can be determined by detecting induction of a cellular second messenger of the target (i.e. intracellular Ca^-+, diacylglycerol, IP₃, etc.), detecting catalytic/enzymatic activity of the target an appropriate substrate, detecting the induction of a reporter gene (comprising an MOLX-responsive regulatory element operatively linked to a nucleic acid encoding a detectable marker, e.g., luciferase), or detecting a cellular response, for example, cell survival, cellular differentiation, or cell proliferation.

In yet another embodiment, an assay ofthe invention is a cell-free assay comprising contacting an MOLX protein or biologically-active portion thereof with a test compound and determining the ability ofthe test compound to bind to the MOLX protein or biologically-active portion thereof. Binding ofthe test compound to the MOLX protein can be determined either directly or indirectly as described above. In one such embodiment, the assay comprises contacting the MOLX protein or biologically-active portion thereof with a known compound which binds MOLX to form an assay mixture, contacting the assay mixture with a test compound, and determining the ability ofthe test compound to interact with an MOLX protein, wherein determining the ability ofthe test compound to interact with an MOLX protein comprises determining the ability ofthe test compound to preferentially bind to MOLX or biologically-active portion thereof as compared to the known compound.

In still another embodiment, an assay is a cell-free assay comprising contacting MOLX protein or biologically-active portion thereof with a test compound and determining the ability ofthe test compound to modulate (e.g. stimulate or inhibit) the activity ofthe MOLX protein or biologically-active portion thereof. Determining the ability ofthe test compound to modulate the activity of MOLX can be accomplished, for example, by determining the ability ofthe MOLX protein to bind to an MOLX target molecule by one ofthe methods described above for determining direct binding. In an alternative embodiment, determining the ability ofthe test compound to modulate the activity of MOLX protein can be accomplished by determining the ability ofthe MOLX protein further modulate an MOLX target molecule. For example, the catalytic/enzymatic activity ofthe target molecule on an appropriate substrate can be determined as described, supra.

In yet another embodiment, the cell-free assay comprises contacting the MOLX protein or biologically-active portion thereof with a known compound which binds MOLX protein to form an assay mixture, contacting the assay mixture with a test compound, and determining the ability ofthe test compound to interact with an MOLX protein, wherein determining the ability ofthe test compound to interact with an MOLX protein comprises determining the ability ofthe MOLX protein to preferentially bind to or modulate the activity of an MOLX target molecule.

The cell-free assays ofthe invention are amenable to use of both the soluble form or the membrane-bound form of MOLX protein. In the case of cell-free assays comprising the membrane-bound form of MOLX protein, it may be desirable to utilize a solubilizing agent such that the membrane-bound form of MOLX protein is maintained in solution.

Examples of such solubilizing agents include non-ionic detergents such as n-octylglucoside, n-dodecylglucoside, n-dodecylmaltoside, octanoyl-N-methylglucamide, decanoyl-N-methylglucamide, Triton^® X-100, Triton^® X-l 14, Thesit^®, Isotridecypoly(ethylene glycol ether)_n, N-dodecyl— N,N-dimethyl-3-ammonio-l-propane sulfonate, 3-(3-cholamidopropyl) dimethylamminiol-1 -propane sulfonate (CHAPS), or 3-(3-cholamidopropyl)dimethylamminiol-2-hydroxy-l -propane sulfonate (CHAPSO).

In more than one embodiment ofthe above assay methods ofthe invention, it may be desirable to immobilize either MOLX protein or its target molecule to facilitate separation of complexed from uncomplexed forms of one or both ofthe proteins, as well as to accommodate automation of the assay. Binding of a test compound to MOLX protein, or interaction of MOLX protein with a target molecule in the presence and absence of a candidate compound, can be accomplished in any vessel suitable for containing the reactants. Examples of such vessels include microtiter plates, test tubes, and micro-centrifuge tubes. In one embodiment, a fusion protein can be provided that adds a domain that allows one or both ofthe proteins to be bound to a matrix. For example, GST-MOLX fusion proteins or GST-target fusion proteins can be adsorbed onto glutathione sepharose beads (Sigma Chemical, St. Louis, MO) or glutathione derivatized microtiter plates, that are then combined with the test compound or the test compound and either the non-adsorbed target protein or MOLX protein, and the mixture is incubated under conditions conducive to complex formation (e.g., at physiological conditions for salt and pH). Following incubation, the beads or microtiter plate wells are washed to remove any unbound components, the matrix immobilized in the case of beads, complex determined either directly or indirectly, for example, as described, supra. Alternatively, the complexes can be dissociated from the matrix, and the level of MOLX protein binding or activity determined using standard techniques.

Other techniques for immobilizing proteins on matrices can also be used in the screening assays ofthe invention. For example, either the MOLX protein or its target molecule can be immobilized utilizing conjugation of biotin and streptavidin. Biotinylated MOLX protein or target molecules can be prepared from biotin-NHS (N-hydroxy-succinimide) using techniques well-known within the art (e.g., biotinylation kit, Pierce Chemicals, Rockford, 111.), and immobilized in the wells of streptavidin-coated 96 well plates (Pierce Chemical). Alternatively, antibodies reactive with MOLX protein or target molecules, but which do not interfere with binding ofthe MOLX protein to its target molecule, can be derivatized to the wells ofthe plate, and unbound target or MOLX protein trapped in the wells by antibody conjugation. Methods for detecting such complexes, in addition to those described above for the GST-immobilized complexes, include immunodetection of complexes using antibodies reactive with the MOLX protein or target molecule, as well as enzyme-linked assays that rely on detecting an enzymatic activity associated with the MOLX protein or target molecule.

In another embodiment, modulators of MOLX protein expression are identified in a method wherein a cell is contacted with a candidate compound and the expression of MOLX mRNA or protein in the cell is determined. The level of expression of MOLX mRNA or protein in the presence ofthe candidate compound is compared to the level of expression of MOLX mRNA or protein in the absence of the candidate compound. The candidate compound can then be identified as a modulator of MOLX mRNA or protein expression based upon this comparison. For example, when expression of MOLX mRNA or protein is greater (i.e., statistically significantly greater) in the presence ofthe candidate compound than in its absence, the candidate compound is identified as a stimulator of MOLX mRNA or protein expression. Alternatively, when expression of MOLX mRNA or protein is less (statistically significantly less) in the presence ofthe candidate compound than in its absence, the candidate compound is identified as an inhibitor of MOLX mRNA or protein expression. The level of MOLX mRNA or protein expression in the cells can be determined by methods described herein for detecting MOLX mRNA or protein.

In yet another aspect ofthe invention, the MOLX proteins can be used as "bait proteins" in a two-hybrid assay or three hybrid assay (.see, e.g., U.S. Patent No. 5,283,317; Zervos, et al, 1993. Cell 72: 223-232; Madura, et al, 1993. J. Biol. Chem. 268: 12046-12054; Bartel, et al, 1993. Biotechniques 14: 920-924; Iwabuchi, et al, 1993.

Oncogene 8: 1693-1696; and Brent WO 94/10300), to identify other proteins that bind to or interact with MOLX ("MOLX-binding proteins" or "MOLX-bp") and modulate MOLX activity. Such MOLX-binding proteins are also likely to be involved in the propagation of signals by the MOLX proteins as, for example, upstream or downstream elements ofthe MOLX pathway.

The two-hybrid system is based on the modular nature of most transcription factors, which consist of separable DNA-binding and activation domains. Briefly, the assay utilizes two different DNA constructs. In one construct, the gene that codes for MOLX is fused to a gene encoding the DNA binding domain of a known transcription factor (e.g., GAL-4). In the other construct, a DNA sequence, from a library of DNA sequences, that encodes an unidentified protein ("prey" or "sample") is fused to a gene that codes for the activation domain ofthe known transcription factor. If the "bait" and the

"prey" proteins are able to interact, in vivo, forming an MOLX-dependent complex, the

DNA-binding and activation domains ofthe transcription factor are brought into close proximity. This proximity allows transcription of a reporter gene (e.g., LacZ) that is operably linked to a transcriptional regulatory site responsive to the transcription factor. Expression ofthe reporter gene can be detected and cell colonies containing the functional transcription factor can be isolated and used to obtain the cloned gene that encodes the protein which interacts with MOLX.

The invention further pertains to novel agents identified by the aforementioned screening assays and uses thereof for treatments as described herein.

Detection Assays

Portions or fragments ofthe cDNA sequences identified herein (and the corresponding complete gene sequences) can be used in numerous ways as polynucleotide reagents. By way of example, and not of limitation, these sequences can be used to: (i) map their respective genes on a chromosome; and, thus, locate gene regions associated with genetic disease; (ii) identify an individual from a minute biological sample (tissue typing); and (iii) aid in forensic identification of a biological sample. Some of these applications are described in the subsections, below.

Chromosome Mapping

Once the sequence (or a portion ofthe sequence) of a gene has been isolated, this sequence can be used to map the location of the gene on a chromosome. This process is called chromosome mapping. Accordingly, portions or fragments ofthe MOLX sequences, SEQ ID NOS: l, 3, 5, 7, 9, 1 1 , 13, 15, 17, 19, 21, 23, 101, 103, 105, 107, 109, 1 12, 1 15, 1 17, 1 19, 121, 124, 135, 137, 139, 141 , 143, 145, 147, 149, 151, 153, 155, 157, 159, 161, 163, 165, and 166, or fragments or derivatives thereof, can be used to map the location ofthe MOLX genes, respectively, on a chromosome. The mapping ofthe MOLX sequences to chromosomes is an important first step in correlating these sequences with genes associated with disease.

Briefly, MOLX genes can be mapped to chromosomes by preparing PCR primers (preferably 15-25 bp in length) from the MOLX sequences. Computer analysis of the MOLX, sequences can be used to rapidly select primers that do not span more than one exon in the genomic DNA, thus complicating the amplification process. These primers can then be used for PCR screening of somatic cell hybrids containing individual human chromosomes. Only those hybrids containing the human gene corresponding to the MOLX sequences will yield an amplified fragment. Somatic cell hybrids are prepared by fusing somatic cells from different mammals (e.g., human and mouse cells). As hybrids of human and mouse cells grow and divide, they gradually lose human chromosomes in random order, but retain the mouse chromosomes. By using media in which mouse cells cannot grow, because they lack a particular enzyme, but in which human cells can, the one human chromosome that contains the gene encoding the needed enzyme will be retained. By using various media, panels of hybrid cell lines can be established. Each cell line in a panel contains either a single human chromosome or a small number of human chromosomes, and a full set of mouse chromosomes, allowing easy mapping of individual genes to specific human chromosomes. See, e.g., D'Eustachio, et al, 1983. Science 220: 919-924. Somatic cell hybrids containing only fragments of human chromosomes can also be produced by using human chromosomes with translocations and deletions.

PCR mapping of somatic cell hybrids is a rapid procedure for assigning a particular sequence to a particular chromosome. Three or more sequences can be assigned per day using a single thermal cycler. Using the MOLX sequences to design oligonucleotide primers, sub-localization can be achieved with panels of fragments from specific chromosomes.

Fluorescence in situ hybridization (FISH) of a DNA sequence to a metaphase chromosomal spread can further be used to provide a precise chromosomal location in one step. Chromosome spreads can be made using cells whose division has been blocked in metaphase by a chemical like colcemid that disrupts the mitotic spindle. The chromosomes can be treated briefly with trypsin, and then stained with Giemsa. A pattern of light and dark bands develops on each chromosome, so that the chromosomes can be identified individually. The FISH technique can be used with a DNA sequence as short as 500 or 600 bases. However, clones larger than 1 ,000 bases have a higher likelihood of binding to a unique chromosomal location with sufficient signal intensity for simple detection. Preferably 1,000 bases, and more preferably 2,000 bases, will suffice to get good results at a reasonable amount of time. For a review of this technique, see, Verma, et al, HUMAN CHROMOSOMES: A MANUAL OF BASIC TECHNIQUES (Pergamon Press, New York 1988).

Reagents for chromosome mapping can be used individually to mark a single chromosome or a single site on that chromosome, or panels of reagents can be used for marking multiple sites and/or multiple chromosomes. Reagents corresponding to noncoding regions ofthe genes actually are preferred for mapping purposes. Coding sequences are more likely to be conserved within gene families, thus increasing the chance of cross hybridizations during chromosomal mapping.

Once a sequence has been mapped to a precise chromosomal location, the physical position ofthe sequence on the chromosome can be correlated with genetic map data. Such data are found, e.g., in McKusick, MENDELIAN INHERITANCE IN MAN, available on-line through Johns Hopkins University Welch Medical Library). The relationship between genes and disease, mapped to the same chromosomal region, can then be identified through linkage analysis (co-inheritance of physically adjacent genes), described in, e.g., Egeland, et al, 1987. Nature, 325: 783-787. Moreover, differences in the DNA sequences between individuals affected and unaffected with a disease associated with the MOLX gene, can be determined. If a mutation is observed in some or all ofthe affected individuals but not in any unaffected individuals, then the mutation is likely to be the causative agent ofthe particular disease. Comparison of affected and unaffected individuals generally involves first looking for structural alterations in the chromosomes, such as deletions or translocations that are visible from chromosome spreads or detectable using PCR based on that DNA sequence. Ultimately, complete sequencing of genes from several individuals can be performed to confirm the presence of a mutation and to distinguish mutations from polymorphisms.

Tissue Typing

The MOLX sequences ofthe invention can also be used to identify individuals from minute biological samples. In this technique, an individual's genomic DNA is digested with one or more restriction enzymes, and probed on a Southern blot to yield unique bands for identification. The sequences ofthe invention are useful as additional DNA markers for RFLP ("restriction fragment length polymorphisms," described in U.S. Patent No. 5,272,057).

Furthermore, the sequences ofthe invention can be used to provide an alternative technique that determines the actual base-by-base DNA sequence of selected portions of an individual's genome. Thus, the MOLX sequences described herein can be used to prepare two PCR primers from the 5'- and 3'-termini ofthe sequences. These primers can then be used to amplify an individual's DNA and subsequently sequence it.

Panels of corresponding DNA sequences from individuals, prepared in this manner, can provide unique individual identifications, as each individual will have a unique set of such DNA sequences due to allelic differences. The sequences ofthe invention can be used to obtain such identification sequences from individuals and from tissue. The MOLX sequences ofthe invention uniquely represent portions of the human genome. Allelic variation occurs to some degree in the coding regions of these sequences, and to a greater degree in the noncoding regions. It is estimated that allelic variation between individual humans occurs with a frequency of about once per each 500 bases. Much ofthe allelic variation is due to single nucleotide polymorphisms (SNPs), which include restriction fragment length polymorphisms (RFLPs).

Each ofthe sequences described herein can, to some degree, be used as a standard against which DNA from an individual can be compared for identification purposes. Because greater numbers of polymorphisms occur in the noncoding regions, fewer sequences are necessary to differentiate individuals. The noncoding sequences can comfortably provide positive individual identification with a panel of perhaps 10 to 1 ,000 primers that each yield a noncoding amplified sequence of 100 bases. If predicted coding sequences, such as those in SEQ ID NOS: l, 3, 5, 7, 9, 1 1, 13, 15, 17, 19, 21, 23, 101, 103, 105, 107, 109, 1 12, 1 15, 1 17, 1 19, 121, 124, 135, 137, 139, 141, 143, 145, 147, 149, 151, 153, 155, 157, 159, 161 , 163, 165, and 166 are used, a more appropriate number of primers for positive individual identification would be 500-2,000.

Predictive Medicine The invention also pertains to the field of predictive medicine in which diagnostic assays, prognostic assays, pharmacogenomics, and monitoring clinical trials are used for prognostic (predictive) purposes to thereby treat an individual prophylactically. Accordingly, one aspect ofthe invention relates to diagnostic assays for determining MOLX protein and/or nucleic acid expression as well as MOLX activity, in the context of a biological sample (e.g., blood, serum, cells, tissue) to thereby determine whether an individual is afflicted with a disease or disorder, or is at risk of developing a disorder, associated with aberrant MOLX expression or activity. The disorders include metabolic disorders, diabetes, obesity, infectious disease, anorexia, cancer-associated cachexia, cancer, neurodegenerative disorders, Alzheimer's Disease, Parkinson's Disorder, immune disorders, and hematopoietic disorders, and the various dyslipidemias, metabolic disturbances associated with obesity, the metabolic syndrome X and wasting disorders associated with chronic diseases and various cancers. The invention also provides for prognostic (or predictive) assays for determining whether an individual is at risk of developing a disorder associated with MOLX protein, nucleic acid expression or activity. For example, mutations in an MOLX gene can be assayed in a biological sample. Such assays can be used for prognostic or predictive purpose to thereby prophylactically treat an individual prior to the onset of a disorder characterized by or associated with MOLX protein, nucleic acid expression, or biological activity.

Another aspect ofthe invention provides methods for determining MOLX protein, nucleic acid expression or activity in an individual to thereby select appropriate therapeutic or prophylactic agents for that individual (referred to herein as "pharmacogenomics"). Pharmacogenomics allows for the selection of agents (e.g., drugs) for therapeutic or prophylactic treatment of an individual based on the genotype of the individual (e.g., the genotype ofthe individual examined to determine the ability ofthe individual to respond to a particular agent.)

Yet another aspect ofthe invention pertains to monitoring the influence of agents (e.g., drugs, compounds) on the expression or activity of MOLX in clinical trials.

These and other agents are described in further detail in the following sections.

Diagnostic Assays

An exemplary method for detecting the presence or absence of MOLX in a biological sample involves obtaining a biological sample from a test subject and contacting the biological sample with a compound or an agent capable of detecting MOLX protein or nucleic acid (e.g., mRNA, genomic DNA) that encodes MOLX protein such that the presence of MOLX is detected in the biological sample. An agent for detecting MOLX mRNA or genomic DNA is a labeled nucleic acid probe capable of hybridizing to MOLX mRNA or genomic DNA. The nucleic acid probe can be, for example, a full-length MOLX nucleic acid, such as the nucleic acid of SEQ ID NOS: 1 , 3, 5, 7, 9, 1 1 , 13, 15, 17, 19, 21 , 23, 101 , 103, 105, 107, 109, 1 12, 1 15, 1 17, 1 19, 121 , 124, 135, 137,

139, 141, 143, 145, 147, 149, 151, 153, 155, 157, 159, 161, 163, 165, and 166, or a portion thereof, such as an oligonucleotide of at least 15, 30, 50, 100, 250 or 500 nucleotides in length and sufficient to specifically hybridize under stringent conditions to MOLX mRNA or genomic DNA. Other suitable probes for use in the diagnostic assays ofthe invention are described herein.

An agent for detecting MOLX protein is an antibody capable of binding to MOLX protein, preferably an antibody with a detectable label. Antibodies can be polyclonal, or more preferably, monoclonal. An intact antibody, or a fragment thereof (e.g. , Fab or

F(ab')₂) can be used. The term "labeled", with regard to the probe or antibody, is intended to encompass direct labeling ofthe probe or antibody by coupling (i.e., physically linking) a detectable substance to the probe or antibody, as well as indirect labeling ofthe probe or antibody by reactivity with another reagent that is directly labeled. Examples of indirect labeling include detection of a primary antibody using a fluorescently-labeled secondary antibody and end-labeling of a DNA probe with biotin such that it can be detected with fluorescently-labeled streptavidin. The term "biological sample" is intended to include tissues, cells and biological fluids isolated from a subject, as well as tissues, cells and fluids present within a subject. That is, the detection method ofthe invention can be used to detect MOLX mRNA, protein, or genomic DNA in a biological sample in vitro as well as in vivo. For example, in vitro techniques for detection of MOLX mRNA include

Northern hybridizations and in situ hybridizations. In vitro techniques for detection of MOLX protein include enzyme linked immunosorbent assays (ELISAs), Western blots, immunoprecipitations, and immunofluorescence. In vitro techniques for detection of MOLX genomic DNA include Southern hybridizations. Furthermore, in vivo techniques for detection of MOLX protein include introducing into a subject a labeled anti-MOLX antibody. For example, the antibody can be labeled with a radioactive marker whose presence and location in a subject can be detected by standard imaging techniques.

In one embodiment, the biological sample contains protein molecules from the test subject. Alternatively, the biological sample can contain mRNA molecules from the test subject or genomic DNA molecules from the test subject. A preferred biological sample is a peripheral blood leukocyte sample isolated by conventional means from a subject.

In another embodiment, the methods further involve obtaining a control biological sample from a control subject, contacting the control sample with a compound or agent capable of detecting MOLX protein, mRNA, or genomic DNA, such that the presence of MOLX protein, mRNA or genomic DNA is detected in the biological sample, and comparing the presence of MOLX protein, mRNA or genomic DNA in the control sample with the presence of MOLX protein, mRNA or genomic DNA in the test sample.

The invention also encompasses kits for detecting the presence of MOLX in a biological sample. For example, the kit can comprise: a labeled compound or agent capable of detecting MOLX protein or mRNA in a biological sample; means for determining the amount of MOLX in the sample; and means for comparing the amount of

MOLX in the sample with a standard. The compound or agent can be packaged in a suitable container. The kit can further comprise instructions for using the kit to detect

MOLX protein or nucleic acid. Prognostic Assays

The diagnostic methods described herein can furthermore be utilized to identify subjects having or at risk of developing a disease or disorder associated with aberrant MOLX expression or activity. For example, the assays described herein, such as the preceding diagnostic assays or the following assays, can be utilized to identify a subject having or at risk of developing a disorder associated with MOLX protein, nucleic acid expression or activity. Alternatively, the prognostic assays can be utilized to identify a subject having or at risk for developing a disease or disorder. Thus, the invention provides a method for identifying a disease or disorder associated with aberrant MOLX expression or activity in which a test sample is obtained from a subject and MOLX protein or nucleic acid (e.g., mRNA, genomic DNA) is detected, wherein the presence of MOLX protein or nucleic acid is diagnostic for a subject having or at risk of developing a disease or disorder associated with aberrant MOLX expression or activity. As used herein, a "test sample" refers to a biological sample obtained from a subject of interest. For example, a test sample can be a biological fluid (e.g., serum), cell sample, or tissue.

Furthermore, the prognostic assays described herein can be used to determine whether a subject can be administered an agent (e.g., an agonist, antagonist, peptidomimetic, protein, peptide, nucleic acid, small molecule, or other drug candidate) to treat a disease or disorder associated with aberrant MOLX expression or activity. For example, such methods can be used to determine whether a subject can be effectively treated with an agent for a disorder. Thus, the invention provides methods for determining whether a subject can be effectively treated with an agent for a disorder associated with aberrant MOLX expression or activity in which a test sample is obtained and MOLX protein or nucleic acid is detected (e.g., wherein the presence of MOLX protein or nucleic acid is diagnostic for a subject that can be administered the agent to treat a disorder associated with aberrant MOLX expression or activity).

The methods ofthe invention can also be used to detect genetic lesions in an MOLX gene, thereby determining if a subject with the lesioned gene is at risk for a disorder characterized by aberrant cell proliferation and/or differentiation. In various embodiments, the methods include detecting, in a sample of cells from the subject, the presence or absence of a genetic lesion characterized by at least one of an alteration affecting the integrity of a gene encoding an MOLX-protein, or the misexpression ofthe

MOLX gene. For example, such genetic lesions can be detected by ascertaining the existence of at least one of: (i) a deletion of one or more nucleotides from an MOLX gene; (ii) an addition of one or more nucleotides to an MOLX gene; (iii) a substitution of one or more nucleotides of an MOLX gene, (iv) a chromosomal rearrangement of an MOLX gene; (v) an alteration in the level of a messenger RNA transcript of an MOLX gene, (vi) aberrant modification of an MOLX gene, such as ofthe methylation pattern ofthe genomic DNA, (vii) the presence of a non-wild-type splicing pattern of a messenger RNA transcript of an MOLX gene, (viii) a non-wild-type level of an MOLX protein, (ix) allelic loss of an MOLX gene, and (x) inappropriate post-translational modification of an MOLX protein. As described herein, there are a large number of assay techniques known in the art which can be used for detecting lesions in an MOLX gene. A preferred biological sample is a peripheral blood leukocyte sample isolated by conventional means from a subject. However, any biological sample containing nucleated cells may be used, including, for example, buccal mucosal cells.

In certain embodiments, detection of the lesion involves the use of a probe/primer in a polymerase chain reaction (PCR) (see, e.g., U.S. Patent Nos. 4,683, 195 and

4,683,202), such as anchor PCR or RACE PCR, or, alternatively, in a ligation chain reaction (LCR) (see, e.g., Landegran, et al, 1988. Science 241 : 1077-1080; and Nakazawa, et al, 1994. Proc. Natl. Acad. Sci. USA 91 : 360-364), the latter of which can be particularly useful for detecting point mutations in the MOLX-gene (.see, Abravaya, et al, 1995. Nucl. Acids Res. 23: 675-682). This method can include the steps of collecting a sample of cells from a patient, isolating nucleic acid (e.g., genomic, mRNA or both) from the cells ofthe sample, contacting the nucleic acid sample with one or more primers that specifically hybridize to an MOLX gene under conditions such that hybridization and amplification ofthe MOLX gene (if present) occurs, and detecting the presence or absence of an amplification product, or detecting the size ofthe amplification product and comparing the length to a control sample. It is anticipated that PCR and/or LCR may be desirable to use as a preliminary amplification step in conjunction with any ofthe techniques used for detecting mutations described herein.

Alternative amplification methods include: self sustained sequence replication (see, Guatelli, et al, 1990. Proc. Natl. Acad. Sci. USA 87: 1874-1878), transcriptional amplification system (see, Kwoh, et al, 1989. Proc. Natl. Acad. Sci. USA 86: 1173-1177); Qβ Replicase (see, Lizardi, et al, 1988. BioTechnology 6: 1197), or any other nucleic acid amplification method, followed by the detection ofthe amplified molecules using techniques well known to those of skill in the art. These detection schemes are especially useful for the detection of nucleic acid molecules if such molecules are present in very low numbers.

In an alternative embodiment, mutations in an MOLX gene from a sample cell can be identified by alterations in restriction enzyme cleavage patterns. For example, sample and control DNA is isolated, amplified (optionally), digested with one or more restriction endonucleases, and fragment length sizes are determined by gel electrophoresis and compared. Differences in fragment length sizes between sample and control DNA indicates mutations in the sample DNA. Moreover, the use of sequence specific ribozymes (see, e.g., U.S. Patent No. 5,493,531) can be used to score for the presence of specific mutations by development or loss of a ribozyme cleavage site.

In other embodiments, genetic mutations in MOLX can be identified by hybridizing a sample and control nucleic acids, e.g., DNA or RNA, to high-density arrays containing hundreds or thousands of oligonucleotides probes. See, e.g., Cronin, et al, 1996. Human Mutation 7: 244-255; Kozal, et al, 1996. Nat. Med. 2: 753-759. For example, genetic mutations in MOLX can be identified in two dimensional arrays containing light-generated DNA probes as described in Cronin, et al, supra. Briefly, a first hybridization array of probes can be used to scan through long stretches of DNA in a sample and control to identify base changes between the sequences by making linear arrays of sequential overlapping probes. This step allows the identification of point mutations. This is followed by a second hybridization array that allows the characterization of specific mutations by using smaller, specialized probe arrays complementary to all variants or mutations detected. Each mutation array is composed of parallel probe sets, one complementary to the wild-type gene and the other complementary to the mutant gene.

In yet another embodiment, any of a variety of sequencing reactions known in the art can be used to directly sequence the MOLX gene and detect mutations by comparing the sequence ofthe sample MOLX with the corresponding wild-type (control) sequence. Examples of sequencing reactions include those based on techniques developed by Maxim and Gilbert, 1977. Proc. Natl. Acad. Sci. USA 74: 560 or Sanger, 1977. Proc. Natl. Acad. Sci. USA 74: 5463. It is also contemplated that any of a variety of automated sequencing procedures can be utilized when performing the diagnostic assays (see, e.g., Naeve, et al, 1995. Biotechniques 19: 448), including sequencing by mass spectrometry (see, e.g., PCT International Publication No. WO 94/16101 ; Cohen, et al, 1996. Adv. Chromatography 36: 127-162; and Griffin, et al, \993. Appl. Biochem. Biotechnol 38: 147-159).

Other methods for detecting mutations in the MOLX gene include methods in which protection from cleavage agents is used to detect mismatched bases in RNA RNA or RNA/DNA heteroduplexes. See, e.g., Myers, et al, 1985. Science 230: 1242. In general, the art technique of "mismatch cleavage" starts by providing heteroduplexes of formed by hybridizing (labeled) RNA or DNA containing the wild-type MOLX sequence with potentially mutant RNA or DNA obtained from a tissue sample. The double-stranded duplexes are treated with an agent that cleaves single-stranded regions ofthe duplex such as which will exist due to basepair mismatches between the control and sample strands. For instance, RNA/DNA duplexes can be treated with RNase and DNA/DNA hybrids treated with Si nuclease to enzymatically digesting the mismatched regions. In other embodiments, either DNA/DNA or RNA/DNA duplexes can be treated with hydroxylamine or osmium tetroxide and with piperidine in order to digest mismatched regions. After digestion of he mismatched regions, the resulting material is then separated by size on denaturing polyacrylamide gels to determine the site of mutation. See, e.g., Cotton, et al, 1988. Proc. Natl. Acad. Sci. USA 85: 4397; Saleeba, et al, 1992. Methods Enzymol. 217: 286-295. In an embodiment, the control DNA or RNA can be labeled for detection. In still another embodiment, the mismatch cleavage reaction employs one or more proteins that recognize mismatched base pairs in double-stranded DNA (so called "DNA mismatch repair" enzymes) in defined systems for detecting and mapping point mutations in MOLX cDNAs obtained from samples of cells. For example, the mutY enzyme of E. coli cleaves A at G/A mismatches and the thymidine DNA glycosylase from HeLa cells cleaves T at G/T mismatches. See, e.g., Hsu, et al, 1994. Carcinogenesis 15: 1657-1662. According to an exemplary embodiment, a probe based on an MOLX sequence, e.g., a wild-type MOLX sequence, is hybridized to a cDNA or other DNA product from a test cell(s). The duplex is treated with a DNA mismatch repair enzyme, and the cleavage products, if any, can be detected from electrophoresis protocols or the like. See, e.g., U.S. Patent No. 5,459,039.

In other embodiments, alterations in electrophoretic mobility will be used to identify mutations in MOLX genes. For example, single strand conformation polymorphism (SSCP) may be used to detect differences in electrophoretic mobility between mutant and wild type nucleic acids. See, e.g., Orita, et al, 1989. Proc. Natl. Acad. Sci. USA: 86: 2766; Cotton, 1993. Mutat. Res. 285: 125-144; Hayashi, 1992. Genet. Anal. Tech. Appl. 9: 73-79. Single-stranded DNA fragments of sample and control MOLX nucleic acids will be denatured and allowed to renature. The secondary structure of single-stranded nucleic acids varies according to sequence, the resulting alteration in electrophoretic mobility enables the detection of even a single base change. The DNA fragments may be labeled or detected with labeled probes. The sensitivity ofthe assay may be enhanced by using RNA (rather than DNA), in which the secondary structure is more sensitive to a change in sequence. In one embodiment, the subject method utilizes heteroduplex analysis to separate double stranded heteroduplex molecules on the basis of changes in electrophoretic mobility. See, e.g., Keen, et al, 1991. Trends Genet. 7: 5. In yet another embodiment, the movement of mutant or wild-type fragments in polyacrylamide gels containing a gradient of denaturant is assayed using denaturing gradient gel electrophoresis (DGGE). See, e.g., Myers, et al, 1985. Nature 313: 495. When DGGE is used as the method of analysis, DNA will be modified to insure that it does not completely denature, for example by adding a GC clamp of approximately 40 bp of high-melting GC-rich DNA by PCR. In a further embodiment, a temperature gradient is used in place of a denaturing gradient to identify differences in the mobility of control and sample DNA. See, e.g., Rosenbaum and Reissner, 1987. Biophys. Chem. 265: 12753. Examples of other techniques for detecting point mutations include, but are not limited to, selective oligonucleotide hybridization, selective amplification, or selective primer extension. For example, oligonucleotide primers may be prepared in which the known mutation is placed centrally and then hybridized to target DNA under conditions that permit hybridization only if a perfect match is found. See, e.g., Saiki, et al, 1986. Nature 324: 163; Saiki, et al, 1989. Proc. Natl. Acad Sci. USA 86: 6230. Such allele specific oligonucleotides are hybridized to PCR amplified target DNA or a number of different mutations when the oligonucleotides are attached to the hybridizing membrane and hybridized with labeled target DNA.

Alternatively, allele specific amplification technology that depends on selective PCR amplification may be used in conjunction with the instant invention. Oligonucleotides used as primers for specific amplification may carry the mutation of interest in the center ofthe molecule (so that amplification depends on differential hybridization; see, e.g., Gibbs, et al, 1989. Nucl. Acids Res. 17: 2437-2448) or at the extreme 3 '-terminus of one primer where, under appropriate conditions, mismatch can prevent, or reduce polymerase extension (see, e.g., Prossner, 1993. Tibtech. 1 1 : 238). In addition it may be desirable to introduce a novel restriction site in the region ofthe mutation to create cleavage-based detection. See, e.g., Gasparini, et al, 1992. Mol. Cell Probes 6: 1. It is anticipated that in certain embodiments amplification may also be performed using Taq ligase for amplification. See, e.g., Barany, 1991. Proc. Natl. Acad. Sci. USA 88: 189. In such cases, ligation will occur only if there is a perfect match at the 3'-terminus ofthe 5' sequence, making it possible to detect the presence of a known mutation at a specific site by looking for the presence or absence of amplification. The methods described herein may be performed, for example, by utilizing pre-packaged diagnostic kits comprising at least one probe nucleic acid or antibody reagent described herein, which may be conveniently used, e.g., in clinical settings to diagnose patients exhibiting symptoms or family history of a disease or illness involving an MOLX gene.

Furthermore, any cell type or tissue, preferably peripheral blood leukocytes, in which MOLX is expressed may be utilized in the prognostic assays described herein. However, any biological sample containing nucleated cells may be used, including, for example, buccal mucosal cells.

Pharmacogenomics

Agents, or modulators that have a stimulatory or inhibitory effect on MOLX activity (e.g., MOLX gene expression), as identified by a screening assay described herein can be administered to individuals to treat (prophylactically or therapeutically) disorders

(The disorders include metabolic disorders, diabetes, obesity, infectious disease, anorexia, cancer-associated cachexia, cancer, neurodegenerative disorders, Alzheimer's Disease,

Parkinson's Disorder, immune disorders, and hematopoietic disorders, and the various dyslipidemias, metabolic disturbances associated with obesity, the metabolic syndrome X and wasting disorders associated with chronic diseases and various cancers.) In conjunction with such treatment, the pharmacogenomics (i.e., the study ofthe relationship between an individual's genotype and that individual's response to a foreign compound or drug) ofthe individual may be considered. Differences in metabolism of therapeutics can lead to severe toxicity or therapeutic failure by altering the relation between dose and blood concentration of the pharmacologically active drug. Thus, the pharmacogenomics ofthe individual permits the selection of effective agents (e.g., drugs) for prophylactic or therapeutic treatments based on a consideration ofthe individual's genotype. Such pharmacogenomics can further be used to determine appropriate dosages and therapeutic regimens. Accordingly, the activity of MOLX protein, expression of MOLX nucleic acid, or mutation content of MOLX genes in an individual can be determined to thereby select appropriate agent(s) for therapeutic or prophylactic treatment ofthe individual.

Pharmacogenomics deals with clinically significant hereditary variations in the response to drugs due to altered drug disposition and abnormal action in affected persons. See e.g., Eichelbaum, 1996. Clin. Exp. Pharmacol. Physiol, 23: 983-985; Linder, 1997. Clin. Chem., 43: 254-266. In general, two types of pharmacogenetic conditions can be differentiated. Genetic conditions transmitted as a single factor altering the way drugs act on the body (altered drug action) or genetic conditions transmitted as single factors altering the way the body acts on drugs (altered drug metabolism). These pharmacogenetic conditions can occur either as rare defects or as polymorphisms. For example, glucose-6-phosphate dehydrogenase (G6PD) deficiency is a common inherited enzymopathy in which the main clinical complication is hemolysis after ingestion of oxidant drugs (anti-malarials, sulfonamides, analgesics, nitrofurans) and consumption of fava beans.

As an illustrative embodiment, the activity of drug metabolizing enzymes is a major determinant of both the intensity and duration of drug action. The discovery of genetic polymorphisms of drug metabolizing enzymes (e.g., N-acetyltransferase 2 (NAT 2) and cytochrome P450 enzymes CYP2D6 and CYP2C19) has provided an explanation as to why some patients do not obtain the expected drug effects or show exaggerated drug response and serious toxicity after taking the standard and safe dose of a drug. These polymorphisms are expressed in two phenotypes in the population, the extensive metabolizer (EM) and poor metabolizer (PM). The prevalence of PM is different among different populations. For example, the gene coding for CYP2D6 is highly polymorphic and several mutations have been identified in PM, which all lead to the absence of functional CYP2D6. Poor metabolizers of CYP2D6 and CYP2C19 quite frequently experience exaggerated drug response and side effects when they receive standard doses. If a metabolite is the active therapeutic moiety, PM show no therapeutic response, as demonstrated for the analgesic effect of codeine mediated by its CYP2D6-formed metabolite morphine. At the other extreme are the so called ultra-rapid metabolizers who do not respond to standard doses. Recently, the molecular basis of ultra-rapid metabolism has been identified to be due to CYP2D6 gene amplification.

Thus, the activity of MOLX protein, expression of MOLX nucleic acid, or mutation content of MOLX genes in an individual can be determined to thereby select appropriate agent(s) for therapeutic or prophylactic treatment ofthe individual. In addition, pharmacogenetic studies can be used to apply genotyping of polymorphic alleles encoding drug-metabolizing enzymes to the identification of an individual's drug responsiveness phenotype. This knowledge, when applied to dosing or drug selection, can avoid adverse reactions or therapeutic failure and thus enhance therapeutic or prophylactic efficiency when treating a subject with an MOLX modulator, such as a modulator identified by one ofthe exemplary screening assays described herein.

Monitoring of Effects During Clinical Trials Monitoring the influence of agents (e.g., drugs, compounds) on the expression or activity of MOLX (e.g., the ability to modulate aberrant cell proliferation and/or differentiation) can be applied not only in basic drug screening, but also in clinical trials. For example, the effectiveness of an agent determined by a screening assay as described herein to increase MOLX gene expression, protein levels, or upregulate MOLX activity, can be monitored in clinical trails of subjects exhibiting decreased MOLX gene expression, protein levels, or downregulated MOLX activity. Alternatively, the effectiveness of an agent determined by a screening assay to decrease MOLX gene expression, protein levels, or downregulate MOLX activity, can be monitored in clinical trails of subjects exhibiting increased MOLX gene expression, protein levels, or upregulated MOLX activity. In such clinical trials, the expression or activity of MOLX and, preferably, other genes that have been implicated in, for example, a cellular proliferation or immune disorder can be used as a "read out" or markers ofthe immune responsiveness of a particular cell.

By way of example, and not of limitation, genes, including MOLX, that are modulated in cells by treatment with an agent (e.g., compound, drug or small molecule) that modulates MOLX activity (e.g., identified in a screening assay as described herein) can be identified. Thus, to study the effect of agents on cellular proliferation disorders, for example, in a clinical trial, cells can be isolated and RNA prepared and analyzed for the levels of expression of MOLX and other genes implicated in the disorder. The levels of gene expression (i.e., a gene expression pattern) can be quantified by Northern blot analysis or RT-PCR, as described herein, or alternatively by measuring the amount of protein produced, by one ofthe methods as described herein, or by measuring the levels of activity of MOLX or other genes. In this manner, the gene expression pattern can serve as a marker, indicative ofthe physiological response ofthe cells to the agent. Accordingly, this response state may be determined before, and at various points during, treatment of the individual with the agent.

In one embodiment, the invention provides a method for monitoring the effectiveness of treatment of a subject with an agent (e.g., an agonist, antagonist, protein, peptide, peptidomimetic, nucleic acid, small molecule, or other drug candidate identified by the screening assays described herein) comprising the steps of (i) obtaining a pre-administration sample from a subject prior to administration ofthe agent; (ii) detecting the level of expression of an MOLX protein, mRNA, or genomic DNA in the preadministration sample; (iii) obtaining one or more post-administration samples from the subject; (iv) detecting the level of expression or activity ofthe MOLX protein, mRNA, or genomic DNA in the post-administration samples; (v) comparing the level of expression or activity ofthe MOLX protein, mRNA, or genomic DNA in the pre-administration sample with the MOLX protein, mRNA, or genomic DNA in the post administration sample or samples; and (vi) altering the administration ofthe agent to the subject accordingly. For example, increased administration ofthe agent may be desirable to increase the expression or activity of MOLX to higher levels than detected, i.e., to increase the effectiveness ofthe agent. Alternatively, decreased administration ofthe agent may be desirable to decrease expression or activity of MOLX to lower levels than detected, i.e., to decrease the effectiveness ofthe agent.

Methods of Treatment

The invention provides for both prophylactic and therapeutic methods of treating a subject at risk of (or susceptible to) a disorder or having a disorder associated with aberrant MOLX expression or activity. The disorders include cardiomyopathy, atherosclerosis, hypertension, congenital heart defects, aortic stenosis, atrial septal defect (ASD), atrioventricular (A-V) canal defect, ductus arteriosus, pulmonary stenosis, subaortic stenosis, ventricular septal defect (VSD), valve diseases, tuberous sclerosis, scleroderma, obesity, transplantation, adrenoleukodystrophy, congenital adrenal hyperplasia, prostate cancer, neoplasm; adenocarcinoma, lymphoma, uterus cancer, fertility, hemophilia, hypercoagulation, idiopathic thrombocytopenic purpura, immunodeficiencies, graft versus host disease, AIDS, bronchial asthma, Crohn's disease; multiple sclerosis, treatment of Albright Hereditary Ostoeodystrophy, and other diseases, disorders and conditions ofthe like.

These methods of treatment will be discussed more fully, below. Disease and Disorders

Diseases and disorders that are characterized by increased (relative to a subject not suffering from the disease or disorder) levels or biological activity may be treated with Therapeutics that antagonize (i.e., reduce or inhibit) activity. Therapeutics that antagonize activity may be administered in a therapeutic or prophylactic manner. Therapeutics that may be utilized include, but are not limited to: ( ) an aforementioned peptide, or analogs, derivatives, fragments or homologs thereof; (ii) antibodies to an aforementioned peptide; (iii) nucleic acids encoding an aforementioned peptide; (iv) administration of antisense nucleic acid and nucleic acids that are "dysfunctional" (i.e., due to a heterologous insertion within the coding sequences of coding sequences to an aforementioned peptide) that are utilized to "knockout" endoggenous function of an aforementioned peptide by homologous recombination (see, e.g., Capecchi, 1989. Science 244: 1288-1292); or (v) modulators ( i.e., inhibitors, agonists and antagonists, including additional peptide mimetic ofthe invention or antibodies specific to a peptide ofthe invention) that alter the interaction between an aforementioned peptide and its binding partner.

Diseases and disorders that are characterized by decreased (relative to a subject not suffering from the disease or disorder) levels or biological activity may be treated with Therapeutics that increase (i.e., are agonists to) activity. Therapeutics that upregulate activity may be administered in a therapeutic or prophylactic manner. Therapeutics that may be utilized include, but are not limited to, an aforementioned peptide, or analogs, derivatives, fragments or homologs thereof; or an agonist that increases bioavailability.

Increased or decreased levels can be readily detected by quantifying peptide and/or RNA, by obtaining a patient tissue sample (e.g., from biopsy tissue) and assaying it in vitro for RNA or peptide levels, structure and/or activity ofthe expressed peptides (or mRNAs of an aforementioned peptide). Methods that are well-known within the art include, but are not limited to, immunoassays (e.g., by Western blot analysis, immunoprecipitation followed by sodium dodecyl sulfate (SDS) polyacrylamide gel electrophoresis, immunocytochemistry, etc.) and/or hybridization assays to detect expression of mRNAs (e.g., Northern assays, dot blots, in situ hybridization, and the like).

Prophylactic Methods

In one aspect, the invention provides a method for preventing, in a subject, a disease or condition associated with an aberrant MOLX expression or activity, by administering to the subject an agent that modulates MOLX expression or at least one MOLX activity. Subjects at risk for a disease that is caused or contributed to by aberrant MOLX expression or activity can be identified by, for example, any or a combination of diagnostic or prognostic assays as described herein. Administration of a prophylactic agent can occur prior to the manifestation of symptoms characteristic ofthe MOLX aberrancy, such that a disease or disorder is prevented or, alternatively, delayed in its progression. Depending upon the type of MOLX aberrancy, for example, an MOLX agonist or MOLX antagonist agent can be used for treating the subject. The appropriate agent can be determined based on screening assays described herein. The prophylactic methods of the invention are further discussed in the following subsections.

Therapeutic Methods

Another aspect ofthe invention pertains to methods of modulating MOLX expression or activity for therapeutic purposes. The modulatory method ofthe invention involves contacting a cell with an agent that modulates one or more ofthe activities of MOLX protein activity associated with the cell. An agent that modulates MOLX protein activity can be an agent as described herein, such as a nucleic acid or a protein, a naturally-occurring cognate ligand of an MOLX protein, a peptide, an MOLX peptidomimetic, or other small molecule. In one embodiment, the agent stimulates one or more MOLX protein activity. Examples of such stimulatory agents include active MOLX protein and a nucleic acid molecule encoding MOLX that has been introduced into the cell. In another embodiment, the agent inhibits one or more MOLX protein activity. Examples of such inhibitory agents include antisense MOLX nucleic acid molecules and anti-MOLX antibodies. These modulatory methods can be performed in vitro (e.g., by culturing the cell with the agent) or, alternatively, in vivo (e.g., by administering the agent to a subject). As such, the invention provides methods of treating an individual afflicted with a disease or disorder characterized by aberrant expression or activity of an MOLX protein or nucleic acid molecule. In one embodiment, the method involves administering an agent (e.g., an agent identified by a screening assay described herein), or combination of agents that modulates (e.g., up-regulates or down-regulates) MOLX expression or activity. In another embodiment, the method involves administering an MOLX protein or nucleic acid molecule as therapy to compensate for reduced or aberrant MOLX expression or activity. Stimulation of MOLX activity is desirable in situations in which MOLX is abnormally downregulated and/or in which increased MOLX activity is likely to have a beneficial effect. One example of such a situation is where a subject has a disorder characterized by aberrant cell proliferation and/or differentiation (e.g., cancer or immune associated disorders). Another example of such a situation is where the subject has a gestational disease (e.g., preclampsia).

Determination of the Biological Effect of the Therapeutic

In various embodiments ofthe invention, suitable in vitro or in vivo assays are performed to determine the effect of a specific Therapeutic and whether its administration is indicated for treatment ofthe affected tissue.

In various specific embodiments, in vitro assays may be performed with representative cells ofthe type(s) involved in the patient's disorder, to determine if a given Therapeutic exerts the desired effect upon the cell type(s). Compounds for use in therapy may be tested in suitable animal model systems including, but not limited to rats, mice, chicken, cows, monkeys, rabbits, and the like, prior to testing in human subjects.

Similarly, for in vivo testing, any ofthe animal model system known in the art may be used prior to administration to human subjects.

Prophylactic and Therapeutic Uses of the Compositions of the Invention

The MOLX nucleic acids and proteins of the invention are useful in potential prophylactic and therapeutic applications implicated in a variety of disorders including, but not limited to: metabolic disorders, diabetes, obesity, infectious disease, anorexia, cancer-associated cancer, neurodegenerative disorders, Alzheimer's Disease, Parkinson's Disorder, immune disorders, hematopoietic disorders, and the various dyslipidemias, metabolic disturbances associated with obesity, the metabolic syndrome X and wasting disorders associated with chronic diseases and various cancers.

As an example, a cDNA encoding the MOLX protein of the invention may be useful in gene therapy, and the protein may be useful when administered to a subject in need thereof. By way of non-limiting example, the compositions ofthe invention will have efficacy for treatment of patients suffering from: metabolic disorders, diabetes, obesity, infectious disease, anorexia, cancer-associated cachexia, cancer, neurodegenerative disorders, Alzheimer's Disease, Parkinson's Disorder, immune disorders, hematopoietic disorders, and the various dyslipidemias. Both the novel nucleic acid encoding the MOLX protein, and the MOLX protein of the invention, or fragments thereof, may also be useful in diagnostic applications, wherein the presence or amount ofthe nucleic acid or the protein are to be assessed. A further use could be as an anti-bacterial molecule (i.e., some peptides have been found to possess anti- bacterial properties). These materials are further useful in the generation of antibodies which immunospecifically-bind to the novel substances ofthe invention for use in therapeutic or diagnostic methods.

Examples

Example 1. Quantitative expression analysis of clones in various cells and tissues The quantitative expression of various clones was assessed using microtiter plates containing RNA samples from a variety of normal and pathology-derived cells, cell lines and tissues using real time quantitative PCR (RTQ PCR; TAQMAN^®). RTQ PCR was performed on a Perkin-Elmer Biosystems ABI PRISM® 7700 Sequence Detection System. Various collections of samples are assembled on the plates, and referred to as Panel 1 (containing cells and cell lines from normal and cancer sources), Panel 2 (containing samples derived from tissues, in particular from surgical samples, from normal and cancer sources), Panel 3 (containing samples derived from a wide variety of cancer sources), Panel 4 (containing cells and cell lines from normal cells and cells related to inflammatory conditions) and Panel CNSD.01 (containing samples from normal and diseased brains).

First, the RNA samples were normalized to constitutively expressed genes such as β -actin and GAPDH. RNA (-50 ng total or ~1 ng polyA+) was converted to cDNA using the TAQMAN^® Reverse Transcription Reagents Kit (PE Biosystems, Foster City, CA; Catalog No. N808-0234) and random hexamers according to the manufacturer's protocol. Reactions were performed in 20 ul and incubated for 30 min. at 48°C. cDNA (5 ul) was then transferred to a separate plate for the TAQMAN® reaction using β-actin and GAPDFI TAQMAN® Assay Reagents (PE Biosystems; Catalog Nos. 431088 IE and 4310884E, respectively) and TAQMAN® universal PCR Master Mix (PE Biosystems; Catalog No. 4304447) according to the manufacturer's protocol. Reactions were performed in 25 ul using the following parameters: 2 min. at 50°C; 10 min. at 95°C; 15 sec. at 95°C/1 min. at 60°C (40 cycles). Results were recorded as CT values (cycle at which a given sample crosses a threshold level of fluorescence) using a log scale, with the difference in RNA concentration between a given sample and the sample with the lowest CT value being represented as 2 to the power of delta CT. The percent relative expression is then obtained by taking the reciprocal of this RNA difference and multiplying by 100. The average CT values obtained for β-actin and GAPDH were used to normalize RNA samples. The RNA sample generating the highest CT value required no further diluting, while all other samples were diluted relative to this sample according to their β -actin /GAPDH average CT values.

Normalized RNA (5 ul) was converted to cDNA and analyzed via TAQMAN® using One Step RT-PCR Master Mix Reagents (PE Biosystems; Catalog No. 4309169) and gene-specific primers according to the manufacturer's instructions. Probes and primers were designed for each assay according to Perkin Elmer Biosystem's Primer Express Software package (version I for Apple Computer's Macintosh Power PC) or a similar algorithm using the target sequence as input. Default settings were used for reaction conditions and the following parameters were set before selecting primers: primer concentration = 250 nM, primer melting temperature (T_m) range = 58°-60° C, primer optimal Tm = 59° C, maximum primer difference = 2° C, probe does not have 5' G, probe T_m must be 10° C greater than primer T_m, amplicon size 75 bp to 100 bp. The probes and primers selected (see below) were synthesized by Synthegen (Houston, TX, USA). Probes were double purified by HPLC to remove uncoupled dye and evaluated by mass spectroscopy to verify coupling of reporter and quencher dyes to the 5' and 3' ends of the probe, respectively. Their final concentrations were: forward and reverse primers, 900 nM each, and probe, 200nM.

PCR conditions:

Normalized RNA from each tissue and each cell line was spotted in each well of a

96 well PCR plate (Perkin Elmer Biosystems). PCR cocktails including two probes (a probe specific for the target clone and another gene-specific probe multiplexed with the target probe) were set up using IX TaqMan™ PCR Master Mix for the PE Biosystems 7700, with 5 mM MgC12, dNTPs (dA, G, C, U at 1 :1 : 1 :2 ratios), 0.25 U/ml AmpliTaq Gold™ (PE Biosystems), and 0.4 UA '1 RNase inhibitor, and 0.25 U/μl reverse transcriptase. Reverse transcription was performed at 48° C for 30 minutes followed by amplification/PCR cycles as follows: 95° C 10 min, then 40 cycles of 95° C for 15 seconds, 60° C for 1 minute.

In the results for Panel 1 , the following abbreviations are used: ca. = carcinoma,

* = established from metastasis, met = metastasis, s cell var= small cell variant, non-s = non-sm =non-small, squam = squamous, pi. eff = pi effusion = pleural effusion, glio = glioma, astro = astrocytoma, and neuro = neuroblastoma.

Panel 2

The plates for Panel 2 generally include 2 control wells and 94 test samples composed of RNA or cDNA isolated from human tissue procured by surgeons working in close cooperation with the National Cancer Institute's Cooperative Human Tissue Network (CHTN) or the National Disease Research Initiative (NDRI). The tissues are derived from human malignancies and in cases where indicated many malignant tissues have "matched margins" obtained from noncancerous tissue just adjacent to the tumor. These are termed normal adjacent tissues and are denoted "NAT" in the results below. The tumor tissue and the "matched margins" are evaluated by two independent pathologists (the surgical pathologists and again by a pathologists at NDRI or CHTN). This analysis provides a gross histopathological assessment of tumor differentiation grade. Moreover, most samples include the original surgical pathology report that provides information regarding the clinical stage ofthe patient. These matched margins are taken from the tissue surrounding (i.e. immediately proximal) to the zone of surgery (designated "NAT", for normal adjacent tissue, in Table RR). In addition, RNA and cDNA samples were obtained from various human tissues derived from autopsies performed on elderly people or sudden death victims (accidents, etc.). These tissues were ascertained to be free of disease and were purchased from various commercial sources such as Clontech (Palo Alto, CA), Research Genetics, and Invitrogen.

RNA integrity from all samples is controlled for quality by visual assessment of agarose gel electropherograms using 28S and 18S ribosomal RNA staining intensity ratio as a guide (2:1 to 2.5: 1 28s: 18s) and the absence of low molecular weight RNAs that would be indicative of degradation products. Samples are controlled against genomic DNA contamination by RTQ PCR reactions run in the absence of reverse transcriptase using probe and primer sets designed to amplify across the span of a single exon.

Panel 3D

The plates of Panel 3D are comprised of 94 cDNA samples and two control samples. Specifically, 92 of these samples are derived from cultured human cancer cell lines, 2 samples of human primary cerebellar tissue and 2 controls. The human cell lines are generally obtained from ATCC (American Type Culture Collection, Manassas, VA), National Cancer Institute or the German tumor cell bank and fall into the following tissue groups: Squamous cell carcinoma of the tongue, breast cancer, prostate cancer, melanoma, epidermoid carcinoma, sarcomas, bladder carcinomas, pancreatic cancers, kidney cancers, leukemias/lymphomas, ovarian/uterine/cervical, gastric, colon, lung and CNS cancer cell lines. In addition, there are two independent samples of cerebellum. These cells are all cultured under standard recommended conditions and RNA extracted using the standard procedures. The cell lines in panel 3D and 1.3D are of the most common cell lines used in the scientific literature.

RNA integrity from all samples is controlled for quality by visual assessment of agarose gel electropherograms using 28S and 18S ribosomal RNA staining intensity ratio as a guide (2: 1 to 2.5:1 28s: 18s) and the absence of low molecular weight RNAs that would be indicative of degradation products. Samples are controlled against genomic DNA contamination by RTQ PCR reactions run in the absence of reverse transcriptase using probe and primer sets designed to amplify across the span of a single exon.

Panel 4

Panel 4 includes samples on a 96 well plate (2 control wells, 94 test samples) composed of RNA (Panel 4r) or cDNA (Panel 4d) isolated from various human cell lines or tissues related to inflammatory conditions. Total RNA from control normal tissues such as colon and lung (Stratagene ,La Jolla, CA) and thymus and kidney (Clontech) were employed. Total RNA from liver tissue from cirrhosis patients and kidney from lupus patients was obtained from BioChain (Biochain Institute, Inc., Hayward, CA). Intestinal tissue for RNA preparation from patients diagnosed as having Crohn's disease and ulcerative colitis was obtained from the National Disease Research Interchange (NDRI) (Philadelphia, PA). Astrocytes, lung fibroblasts, dermal fibroblasts, coronary artery smooth muscle cells, small airway epithelium, bronchial epithelium, microvascular dermal endothelial cells, microvascular lung endothelial cells, human pulmonary aortic endothelial cells, human umbilical vein endothelial cells were all purchased from Clonetics (Walkersville, MD) and grown in the media supplied for these cell types by Clonetics. These primary cell types were activated with various cytokines or combinations of cytokines for 6 and/or 12- 14 hours, as indicated. The following cytokines were used; IL-1 beta at approximately 1-5 ng/ml, TNF alpha at approximately 5-10 ng/ml, IFN gamma at approximately 20-50 ng/ml, IL-4 at approximately 5-10 ng/ml, IL-9 at approximately 5-10 ng/ml, IL-13 at approximately 5-10 ng/ml. Endothelial cells were sometimes starved for various times by culture in the basal media from Clonetics with 0.1% serum.

Mononuclear cells were prepared from blood of employees a CuraGen Corporation, using Ficoll. LAK cells were prepared from these cells by culture in DMEM 5% FCS (Hyclone), 100 μM non essential amino acids (Gibco/Life Technologies, Rockville, MD), 1 mM sodium pyruvate (Gibco), mercaptoethanol 5.5 x 10° M (Gibco), and 10 mM Hepes (Gibco) and Interleukin 2 for 4-6 days. Cells were then either activated with 10-20 ng/ml PMA and 1-2 μg/ml ionomycin, IL-12 at 5-10 ng/ml, IFN gamma at 20-50 ng/ml and IL-18 at 5-10 ng/ml for 6 hours. In some cases, mononuclear cells were cultured for 4-5 days in DMEM 5% FCS (Hyclone), 100 μM non essential amino acids (Gibco), 1 mM sodium pyruvate (Gibco), mercaptoethanol 5.5 x 10° M (Gibco), and 10 mM Hepes (Gibco) with PHA (phytohemagglutinin) or PWM (pokeweed mitogen) at approximately 5 μg/ml. Samples were taken at 24, 48 and 72 hours for RNA preparation. MLR (mixed lymphocyte reaction) samples were obtained by taking blood from two donors, isolating the mononuclear cells using Ficoll and mixing the isolated mononuclear cells 1 :1 at a final concentration of approximately 2x10⁶ cells/ml in DMEM 5% FCS (Hyclone), 100 μM non essential amino acids (Gibco), 1 mM sodium pyruvate (Gibco), mercaptoethanol (5.5 x 10^"5 M) (Gibco), and 10 mM Hepes (Gibco). The MLR was cultured and samples taken at various time points ranging from 1- 7 days for RNA preparation. Monocytes were isolated from mononuclear cells using CD 14 Miltenyi Beads, +ve VS selection columns and a Vario Magnet according to the manufacturer's instructions. Monocytes were differentiated into dendritic cells by culture in DMEM 5% fetal calf serum (FCS) (Hyclone, Logan, UT), 100 μiM non essential amino acids (Gibco), 1 mM sodium pyruvate (Gibco), mercaptoethanol 5.5 x 10^"5 M (Gibco), and 10 mM Hepes (Gibco), 50 ng/ml GMCSF and 5 ng/ml IL-4 for 5-7 days. Macrophages were prepared by culture of monocytes for 5-7 days in DMEM 5% FCS (Hyclone), 100 μM non essential amino acids (Gibco), 1 mM sodium pyruvate (Gibco), mercaptoethanol 5.5 x 10^"5 M (Gibco), 10 M Hepes (Gibco) and 10% AB Human Serum or MCSF at approximately 50 ng/ml. Monocytes, macrophages and dendritic cells were stimulated for 6 and 12-14 hours with lipopolysaccharide (LPS) at 100 ng/ml. Dendritic cells were also stimulated with anti-CD40 monoclonal antibody (Pharmingen) at 10 μg/ml for 6 and 12-14 hours.

CD4 lymphocytes, CD8 lymphocytes and NK cells were also isolated from mononuclear cells using CD4, CD8 and CD56 Miltenyi beads, positive VS selection columns and a Vario Magnet according to the manufacturer's instructions. CD45RA and CD45RO CD4 lymphocytes were isolated by depleting mononuclear cells of CD8, CD56, CD14 and CD19 cells using CD8, CD56, CD14 and CD19 Miltenyi beads and positive selection. Then CD45RO beads were used to isolate the CD45RO CD4 lymphocytes with the remaining cells being CD45RA CD4 lymphocytes. CD45RA CD4, CD45RO CD4 and CD8 lymphocytes were placed in DMEM 5% FCS (Hyclone), 100 μM non essential amino acids (Gibco), 1 mM sodium pyruvate (Gibco), mercaptoethanol 5.5 x 10° M (Gibco), and 10 mM Hepes (Gibco) and plated at 10⁶ cells/ml onto Falcon 6 well tissue culture plates that had been coated overnight with 0.5 μg/ml anti-CD28 (Pharmingen) and 3 iig/ml anti-CD3 (OKT3, ATCC) in PBS. After 6 and 24 hours, the cells were harvested for RNA preparation. To prepare chronically activated CD8 lymphocytes, we activated the isolated CD8 lymphocytes for 4 days on anti-CD28 and anti-CD3 coated plates and then harvested the cells and expanded them in DMEM 5% FCS (Hyclone), 100 μM non essential amino acids (Gibco), 1 mM sodium pyruvate (Gibco), mercaptoethanol 5.5 x 10° M (Gibco), and 10 M Hepes (Gibco) and IL-2. The expanded CD8 cells were then activated again with plate bound anti-CD3 and anti-CD28 for 4 days and expanded as before. RNA was isolated 6 and 24 hours after the second activation and after 4 days of the second expansion culture. The isolated NK cells were cultured in DMEM 5% FCS (Hyclone), 100 μM non essential amino acids (Gibco), 1 mM sodium pyruvate (Gibco), mercaptoethanol 5.5 x 10° M (Gibco), and 10 mM Hepes (Gibco) and IL-2 for 4-6 days before RNA was prepared.

To obtain B cells, tonsils were procured from NDRI. The tonsil was cut up with sterile dissecting scissors and then passed through a sieve. Tonsil cells were then spun down and resupended at 10⁶ cells/ml in DMEM 5% FCS (Hyclone), 100 μM non essential amino acids (Gibco), 1 mM sodium pyruvate (Gibco), mercaptoethanol 5.5 x 10^"D M (Gibco), and 10 mM Hepes (Gibco). To activate the cells, we used PWM at 5 μg/ml or anti-CD40 (Pharmingen) at approximately 10 μg/ml and IL-4 at 5-10 ng/ml. Cells were harvested for RNA preparation at 24,48 and 72 hours. To prepare the primary and secondary Thl/Th2 and Trl cells, six-well Falcon plates were coated overnight with 10 μg/ml anti-CD28 (Pharmingen) and 2 μg/ml OKT3 (ATCC), and then washed twice with PBS. Umbilical cord blood CD4 lymphocytes

5 6

(Poietic Systems, German Town, MD) were cultured at 10 -10 cells/ml in DMEM 5% FCS (Hyclone), 100 μiM non essential amino acids (Gibco), 1 mM sodium pyruvate (Gibco), mercaptoethanol 5.5 x 10° M (Gibco), 10 mM Hepes (Gibco) and IL-2 (4 ng/ml). IL-12 (5 ng/ml) and anti-IL4 (1 Dg/ml) were used to direct to Thl, while IL-4 (5 ng/ml) and anti-IFN gamma (1 l.jg/ml) were used to direct to Th2 and IL-10 at 5 ng/ml was used to direct to Trl . After 4-5 days, the activated Thl, Th2 and Trl lymphocytes were washed once in DMEM and expanded for 4-7 days in DMEM 5% FCS (Hyclone), 100 μM non essential amino acids (Gibco), 1 mM sodium pyruvate (Gibco), mercaptoethanol 5.5 x 10° M (Gibco), 10 mM Hepes (Gibco) and IL-2 (1 ng/ml). Following this, the activated Th l, Th2 and Trl lymphocytes were re-stimulated for 5 days with anti-CD28/OKT3 and cytokines as described above, but with the addition of anti-CD95L (1 ϋg/ml) to prevent apoptosis. After 4-5 days, the Thl, Th2 and Trl lymphocytes were washed and then expanded again with IL-2 for 4-7 days. Activated Thl and Th2 lymphocytes were maintained in this way for a maximum of three cycles. RNA was prepared from primary and secondary Thl, Th2 and Trl after 6 and 24 hours following the second and third activations with plate bound anti-CD3 and anti-CD28 mAbs and 4 days into the second and third expansion cultures in Interleukin 2. The following leukocyte cells lines were obtained from the ATCC: Ramos, EOL-1,

KU-812. EOL cells were further differentiated by culture in 0.1 mM dbcAMP at 5 xlO⁵ cells/ml for 8 days, changing the media every 3 days and adjusting the cell concentration to 5 xlO³ cells/ml. For the culture of these cells, we used DMEM or RPMI (as recommended by the ATCC), with the addition of 5% FCS (Hyclone), 100 μM non essential amino acids (Gibco), 1 mM sodium pyruvate (Gibco), mercaptoethanol 5.5 x 10^"5 M (Gibco), 10 mM Hepes (Gibco). RNA was either prepared from resting cells or cells activated with PMA at 10 ng/ml and ionomycin at 1 μg/ml for 6 and 14 hours. Keratinocyte line CCD 106 and an airway epithelial tumor line NCI-H292 were also obtained from the ATCC. Both were cultured in DMEM 5% FCS (Hyclone), 100 μM non essential amino acids (Gibco), 1 mM sodium pyruvate (Gibco), mercaptoethanol 5.5 x 10° M (Gibco), and 10 mM Hepes (Gibco). CCD 1 106 cells were activated for 6 and 14 hours with approximately 5 ng/ml TNF alpha and 1 ng/ml IL-1 beta, while NCI-H292 cells were activated for 6 and 14 hours with the following cytokines: 5 ng/ml IL-4, 5 ng/ml IL-9, 5 ng/ml IL-13 and 25 ng/ml IFN gamma.

For these cell lines and blood cells, RNA was prepared by lysing approximately 10⁷ cells/ml using Trizol (Gibco BRL). Briefly, 1/10 volume of bromochloropropane (Molecular Research Corporation) was added to the RNA sample, vortexed and after 10 minutes at room temperature, the tubes were spun at 14,000 rpm in a Sorvall SS34 rotor. The aqueous phase was removed and placed in a 15 ml Falcon Tube. An equal volume of isopropanol was added and left at -20 degrees C overnight. The precipitated RNA was spun down at 9,000 rpm for 15 min in a Sorvall SS34 rotor and washed in 70% ethanol. The pellet was redissolved in 300 μl of RNAse-free water and 35 μl buffer (Promega) 5 μl DTT, 7 μl RNAsin and 8 μl DNAse were added. The tube was incubated at 37 degrees C for 30 minutes to remove contaminating genomic DNA, extracted once with phenol chloroform and re-precipitated with 1/10 volume of 3 M sodium acetate and 2 volumes of 100% ethanol. The RNA was spun down and placed in

RNAse free water. RNA was stored at -80 degrees C.

Panel CNSD.01

The plates for Panel CNSD.01 include two control wells and 94 test samples comprised of cDNA isolated from postmortem human brain tissue obtained from the Harvard Brain Tissue Resource Center. Brains are removed from calvaria of donors between 4 and 24 hours after death, sectioned by neuroanatomists, and frozen at -80°C in liquid nitrogen vapor. All brains are sectioned and examined by neuropathologists to confirm diagnoses with clear associated neuropathology. Disease diagnoses are taken from patient records. The panel contains two brains from each of the following diagnoses: Alzheimer's disease, Parkinson's disease, Huntington's disease, Progressive Supernuclear Palsy, Depression, and "Normal controls". Within each of these brains, the following regions are represented: cingulate gyrus, temporal pole, globus palladus, substantia nigra, Brodman Area 4 (primary motor strip), Brodman Area 7 (parietal cortex), Brodman Area 9 (prefrontal cortex), and Brodman area 17 (occipital cortex). Not all brain regions are represented in all cases; e.g., Huntington's disease is characterized in part by neurodegeneration in the globus palladus, thus this r region is impossible to obtain from confirmed Huntington's cases. Likewise Parkinson's disease is characterized by degeneration of the substantia nigra making this region more difficult to obtain. Normal control brains were examined for neuropathology and found to be free of any pathology consistent with neurodegeneration.

RNA integrity from all samples is controlled for quality by visual assessment of agarose gel electropherograms using 28S and 18S ribosomal RNA staining intensity ratio as a guide (2: 1 to 2.5: 1 28s: l 8s) and the absence of low molecular weight RNAs that would be indicative of degradation products. Samples are controlled against genomic

DNA contamination by RTQ PCR reactions run in the absence of reverse transcriptase using probe and primer sets designed to amplify across the span of a single exon.

In the labels employed to identify tissues in the CNS panel, the following abbreviations are used:

PSP = Progressive supranuclear palsy

Sub Nigra = Substantia nigra Glob Palladus= Globus palladus Temp Pole = Temporal pole

Cing Gyr = Cingulate gyrus BA 4 = Brodman Area 4

A. MOLla Expression of gene SC29674552_EXT was assessed using the primer-probe sets Ag267 and Agl308, described in Tables 10 and 11. Results of the RTQ-PCR runs are shown in Tables 12, 13, 14, 15, and 16

Table 10. Probe Name Ag267

Table 11. Probe Name: Agl308

Table 12. Panel 1

Table 13. Panel 1.2

Table 14. Panel 2D

Table 15. Panel 2.2

Table 16. Panel 4D

Panel 1 Summary: Ag267 Among the normal tissues on this panel, highest expression of the MOLla gene is detected in testis (CT value = 25) and adipose. High expression in adipose might suggest that the MOLla gene plays a role in the development of metabolic diseases, such as obesity or diabetes. In addition, expression of this gene is high in a renal cancer cell line (CT value = 25). Moderate expression of the MOLla gene is also seen in most regions of normal brain. Strikingly, the MOLla transcript appears at much higher levels in a number of CNS cancer cell lines. Therefore, inhibition of the MOLla gene product using a monoclonal antibody and/or small molecule therapeutic may be useful for the treatment of some renal cell and CNS carcinomas.

Panel 1.2 Summary: Ag267 Expression of the MOLla gene is highest in the cerebral cortex (CT value = 25) with more moderate expression detected in most other regions of normal brain, suggesting a role for this gene in neurological function. Consistent with the results seen in Panel 1, this gene is strikingly overexpressed in a number of CNS cancer cell lines (specifically glioma and astrocytoma). Moderate overexpression of the MOLla gene is also detected in renal cell cancer and lung cancer cell lines relative to the normal controls. The MOLla gene product displays moderate similarity to the Notch protein that has been shown to be involved in cell signalling and has been implicated in oncogenesis. Therefore, the MOLla gene may be a good marker for CNS or other cancers and would potentially serve as a good drug target for the treatment of certain cancers. This gene is also well expressed in several metabolic tissues (specifically adipose, liver and pancreas) and may thus have application for the treatment of metabolic diseases such as diabetes and obesity. Of particular interest is the good expression (CT value = 30.6) in pancreas. The human pancreas-specific gene SEL-11 is thought to be a negative regulator of the notch receptor (Harada, Y. et al. J Hum Genet 44(5):330-6, 1999). Thus, the notch-like MOLla gene and notch receptor may have potential therapeutic use in diseases involving the pancreas.

Panel 1.3D Summary: Ag267 Among normal tissues, highest MOLl a transcript levels are found in adipose (CT value = 30). As was seen for Panels 1 and 1.2, moderate expression of this gene is detected in most regions of normal brain and the gene is strikingly over expressed in a number of CNS cancer cell lines. In general, expression of the MOLla gene appears to be higher in cell lines when compared to tissue samples. A cluster of expression associated with brain, breast and renal cancer cell lines is evident. Thus, the expression of this gene could be associated with cancer cells when compared to normal, since these cell lines are derived from cancers. Alternatively, the expression of this gene could be associated with cell division, since a high percentage of cells in culture are actively dividing when compared to cells in tissue.

Panel 2D Summary: Ag267 Expression of the MOLla gene in panel 2D appears to be widespread across most of the samples. However, there seems to be significant dysregulation in breast cancers when compared to normal adjacent tissues. Thus, therapeutic modulation of this gene might show utility in the treatment of breast cancers.

Panel 2.2 Summary: Agl308 The expression of this gene appears to be widespread across most ofthe samples in panel 2.2. In a couple of instances of renal cell cancer, there seems to be significant dysregulation ofthe expression of this gene when compared to normal adjacent tissue. Thus, therapeutic modulation of this gene might be useful in the treatment of a sub-set of renal cancers.

Panel 4D Summary: Ag267/Agl308 The MOL la transcript is broadly expressed in fibroblasts, keratinocytes, B cells, and T cells, although at a moderate level. High expression of the transcript is also found in monocytes, whether activated or not. In addition, the transcript is up-regulated (7 fold) in keratinocytes and small airway epitheliun by treatment with TNFa and IL-1. The Notch-like protein encoded by the

MOLla gene may regulate cell survival based on its homology to other Notch proteins.

Therefore, protein therapeutics (agonist or antagonists) against the MOLla gene product may be beneficial in the treatment of lung diseases, such as asthma and emphysema, or in the treatment of skin diseases, such as psoriasis and contact sensitivity.

B. MOL2

Expression of gene MOL2 was assessed using the primer-probe set Ag2120, described in Table 17. Results ofthe RTQ-PCR runs are shown in Tables 18, 19, 20, and 21

Table 17. Probe Name Ag2120

Table 18. Panel 1.3D

Table 19. Panel 2D

Table 20. Panel 4D

Table 21. Panel CNSD.01

Panel 1.3D Summary: Ag2120 Two replicate experiments using the same probe and primer set show very comparable results. Expression of the MOL2 gene is highest in the cerebral cortex (CT value = 29). Moderate expression is detected in all other regions ofthe brain except thalamus and substantia nigra; this observation suggests that the MOL2 gene may be associated with normal brain homeostasis. Thus, this protein shows a brain- preferential expression; see write-up on Panel CNS.01 for discussion of utility. In addition, expression of the MOL2 gene appears to be down-regulated in CNS cancer cell lines. Overexpression ofthe MOL2 gene is also detected in several lung cancer cell lines relative to normal control. Therefore, this gene might be a good target for the detection or treatment of CNS and lung cancers. Panel 2D Summary: Ag2120 Two replicate experiments using the same probe and primer set show very comparable results. Expression ofthe MOL2 gene in panel 2D reveals an association of expression in thyroid, breast and kidney cancers when compared to their respective normal adjacent tissues. Thus, therapeutic modulation of this gene with inhibitory monoclonal antibodies and/or small moleculte therapeutics may show utility in treatment of these diseases. In addition, the MOL2 gene might be useful as a marker for thyroid, breast and kidney cancers.

Panel 4D Summary: Ag 2120 The MOL2 gene is expressed at highest levels in the thymus (CT value =31), In addition, the transcript is also expressed in eosinophils, monocytes, macrophages and coronary artery. Interestingly, it is down regulated in LPS- treated monocytes and to a lesser degree in LPS treated macrophages. Therefore, protein therapeutics (agonists or antagonists) designed against the protein encoded for by this transcript could reduce inflammatory process observed in asthma, emphysema, osteoarthritis and sepsis. Panel CNSD.01 Summary: Ag2120 The insulin and insulin-like growth factors belong to a family of polypeptides essential for proper regulation of physiologic processes such as energy metabolism, cell proliferation, development, and differentiation. The insulin-like growth factors bind to IGF with high affinity and compete with the IGF receptor for IGF binding. Transgenic mice overexpressing insulin-like growth factor binding proteins (IGFBPs) tend to show brain developmental abnormalities, suggesting a role for these proteins in neurodevelopment. Furthermore, treatment with glycosaminoglycans (which increases muscle re-innervation after motor neuron death) upregulates serum levels of both IGF and IGFBP. Thus, the novel IGFBP encoded by the MOL2 gene may be useful in the treatment of diseases such as ALS, multiple sclerosis, and peripheral nerve injury on the basis of its homology to other established IGFBPs. The expression profile of this gene suggests that it is expressed preferentially in the brain, with highest levels in the cerebral cortex and hippocampus, two regions that are known to degenerate in Alzheimer's disease. Examination of the expression profile on Panel CNS.01 shows that most regions of both control and diseased brains express this protein; however the levels are decreased in the motor cortex in progressive supranuclear palsy and depression. Thus, this protein may additionally be of use in the treatment of Alzheimer's disease, progressive supranuclear palsy, and depression. C. MOL3a

Expression of gene MOL3a was assessed using the primer-probe set Agl493, described in Table 22. Results of the RTQ-PCR runs are shown in Tables 23, 24, 25, and 26.

Table 22. Probe Name Agl493

Table 23. Panel 1.2

Table 24. Panel 1.3D

Table 25. Panel 2D

Table 26. Panel 4.1D

Table 27. Panel CNSD.01

Panel 1.2 Summary: Agl493 The high expression ofthe MOL3a gene seen in adipose (CT value = 25) is most likely skewed due to genomic DNA contamination in this sample. Otherwise, the gene is expressed mainly in normal tissues, including brain (particularly cerebral cortex), kidney, and prostate. Expression ofthe MOL3a gene in skeletal muscle and liver may suggest function in metabolic diseases, including obesity and diabetes. Furthermore, MOL3a expression is down regulated in a number of tumor cell lines relative to the normal controls suggesting a potential utility of this gene in the treatment of cancer.

Panel 1.3D Summary: Agl493 In this panel, highest expression of the MOL3a gene is detected in the amygdala ofthe brain (CT value = 29.6). This may suggest that the MOL3a gene plays a role in normal brain function, including fear and anxiety response. In addition, high expression is also observed in adipose and bone marrow suggesting potential roles in metabolic and immune function. Overall, expression ofthe MOL3a gene in panel 1.3D reveals that it is associated mostly with normal tissues. In a couple of instances, the expression of this gene is seen in clusters of cell lines, specifically in breast and ovarian cancer cell lines. Thus, therapeutic modulation of expression of this gene may be of utility in the treatment breast and ovarian cancers. Alternatively, replacement ofthe MOL3a protein that is missing from some cancer cells using recombinant protein might provide a useful treatment for these types of cancers. Panel 2D Summary: Agl493 Expression ofthe MOL3a gene is highest in thyroid and appears to be widespread across many samples on Panel 2D. However, overall there appears to be generally higher expression in normal tissues when compared to cancerous counterparts. Thus, therapeutic modulation of this gene or gene product might show utility for a range of oncology indications. Semaphorins and their receptors are known signals for axon guidance; they are also suspected to regulate developmental processes involving cell migration and morphogenesis, and have been implicated in immune function and tumor progression.

Panel 4.1D Summary: Agl493 The MOL3a transcript is highly expressed in a B cell line as well as in B cells stimulated with CD40L and IL4. Expression of this transcript is also found to a lesser degree in monocytes and macrophages independently of their activation status. Of interest, CD 100, which is an activation molecule on T cells, is a member of the semaphorin protein family. The semaphorin B-like protein encoded by the MOL3a transcript could therefore also serve as a B cell activation marker. The semaphorin family has additionally been reported to play a role in che otaxis. Thus, protein therapeutics or monoclonal antibodies raised against the MOL3a protein, could inhibit spontaneous and chemokine induced migration of B cells and monocytes and potentially regulate B cell differentiation and B cell isotype switching. Regulation of this molecule by protein therapeutics or monoclonal antibodies could also function to regulate immunity and be important for the treatment of autoimmune diseases, allergic diseases, and immune rejection in transplantation. In support of this hypothesis, recent studies indicate that semaphorins bind with high affinity to at least two different receptor families and are biologically active on immune cells as well as neuronal cells (Curr Opin Immunol 1999 Aug;l l(4):387-91). Panel CNSD.01 Summary: Agl493 Semaphorins can act as axon guidance proteins, specifically through their ability to act as chemorepellents that inhibit CNS regenerative capacity. Although there is considerable variance between individuals in MOL3a gene expression levels in this panel, levels of this protein are reduced to less than 1/3 of that seen in controls in the temporal cortex of Alzheimer's patients (which shows marked synaptogenic loss in mid to late phases of the disease) as well as in diseases not associated with neurodegeneration of the temporal cortex. Therefore, manipulation of levels of this protein may be of use in inducing a compensatory synaptogenic response to neuronal death in Alzheimer's disease. D. MOL4a

Expression of gene MOL4a was assessed using the primer-probe set Agl216, described in Table 28. Results of the RTQ-PCR runs are shown in Tables 29, 30, 31, and

32.

Table 28. Probe Name: Agl216

Table 29. Panel 1.2

Table 30. Panel 2.2

Table 31. Panel 4D

Panel 32. Panel CNSD.01

Panel 1.2 Summary: Agl216 The MOL4a gene is well expressed in a variety of normal tissues including kidney, heart, brain, thymus and lung. Of interest is the robust expression in activated endothelial cells, which may indicate that this gene is important for angiogenesis or lymphocyte trafficking. Inflammatory lymphocytes preferentially traffic into tissues by crossing activated endothelium. Expression of the MOL4a gene appears to be up regulated in renal cell carcinomas. In contrast, expression of the MOL4a gene is down regulated in a number of cancer cell lines (including pancreatic, CNS, breast, and lung) relative to the normal controls. No expression of this gene is detected in a variety of melanoma cell lines. Therefore, modulation of MOL4a gene function may provide an effective treatment for a variety of cancers.

Panel 2.2 Summary: Agl216 Expression ofthe MOL4a gene appears to be associated with kidney cancers. This is in good agreement with the data obtained in Panel 1.2 and suggests that therapeutic modulation of this gene using inhibitory monoclonal antibodies or small molecules may prove useful in the treatment of kidney cancers. In addition, the MOL4a gene may be a useful marker for the detection of renal cell carcinomas.

Panel 4D Summary: Agl216 Two replicate experiments using the same probe and primer set were in good agreement. The MOL4a transcript is highly expressed in thymus. To a much lesser degree, the transcript is also expressed in the lung as well as in small airway epithelium treated with TNF-a and IL-lb. Therefore, protein therapeutics designed against the protein encoded for by this transcript could reduce inflammation in asthma or other lung disease such as emphysema.

Panel CNSD.01 Summary: Agl216 Semaphorins can act as axon guidance proteins, specifically through their ability to act as chemorepellents that inhibit CNS regenerative capacity. Manipulation of levels ofthe MOL4a semaphorin-like protein may therefore be of use in inducing a compensatory synaptogenic response to neuronal death in Alzheimer's disease, Parkinson's disease, Huntington's disease, spinocerebellar ataxia, progressive supranuclear palsy, multiple sclerosis, ALS, head trauma, stroke, or any other disease/condition associated with neuronal loss. MOL4b

Table A Agl216

Table AA. Panel 1.2

Table AB. Panel 2.2

Table AC. Panel 4D

Potential Role(s) of MOL4b in Tumorgenesis: Semaphorins are cell surface receptors involved in axon guidance molecules with chemorepulsive activity, and are suggested to play a major role in navigating axonal networks throughout development into their correct destinations. They have been found to act as receptor for neurophilin both in neuronal and non-neuronal cell, specifically endothelial cells. Panel 1 indicate that MOL4b is induced in activated endothelial cells and it is expressed by tumor cell derived from Kidney and ovarian tumors. It therefore likely that in these cell types, MOL4b expression contributes to migration and survival activities Impact of therapeutic targeting of MOL4b: Therapeutic targeting with a human monoclonal antibody of MOL4b might block the migration of cancer cells, and/or supporting stromal elements, specifically endothelial cells, and promote cell death rather than cell survival especially in those cancer types, like kidney and ovarian tumors where the gene is overexpressed in the tumor compared to the normal adjacent tissue

E. MOL5a

Expression of gene MOL5a was assessed using the primer-probe sets Agl215 and Agl382 (identical sequences), described in Tables 33 and 34. Results of the RTQ-PCR runs are shown in Tables 35, 36, and 37.

Table 33. Probe Name Agl215/Agl382

Table 34. Panel 1.2

Table 35. Panel 2.2

Panel 36. Panel 4D

Relative Relative

Expression(%_ )|Expression(%)

4Dtm2070f_ 4Dtm2425t_

Tissue Name ag!215 ag!382

Table 37. Panel CNSD.01

Panel 1.2 Summary: Agl215/Agl382 Two replicate experiments were performed using probe and primer sets of identical sequences; however, relatively disparate results were obtained on this panel. For Agl215, the MOL5a gene is expressed at high levels across most of the tissues on this panel with highest expression in treated endothelial cells (CT value = 23). For Agl382, the MOL5a gene is expressed at high levels across most ofthe tissues on this panel with highest expression in an ovarian cancer cell line (CT value = 22). To summarize the expression profile, there appears to be widespread expression of the MOL5a gene in a number of tissues and cell lines. Furthermore, the expression of this gene seems to be associated with reproductive tissues and cancer cell lines whose origins are such. For instance, there is significant expression in ovarian cell lines, breast cell lines and placenta tissue. There is also moderate expression in kidney tissues and lung cell lines.

Panel 2.2 Summary: Agl215 There appears to be widespread expression of the MOL5a gene in the samples of panel 2.2. Specifically, there seems to be an association of expression in breast cancer and normal ovarian tissue. This is reasonably consistent with the results obtained from Panel 1.2. In addition, there is also some correlation with expression in normal kidney tissue when compared to kidney cancers, also consistent with the observations in Panel 1.2. Thus, therapeutic modulation of this gene or gene product might show utility in the treatment of breast cancer, ovarian cancer or kidney cancer.

Panel 4D Summary: Agl215/Agl382 Results from two replicate experiments performed using probe and primer sets of identical sequences are in reasonable agreement. The MOL5a transcript is widely expressed in cell lines from this panel (CT values = 25- 30), including thymus, lung, muco-epidermoid cell lines, fibroblasts from diverse origin, and activated T cells. In addition, the MOL5a gene is expressed in normal colon but not in colons from patients with Crohn's disease or colitis. Thus, protein therapeutics designed with the putative semaphorin encoded for by this protein could reduce or eliminate inflammation and tissue destruction due to IBD. High expression of this transcript was found on primary resting Thl T cells, and also primary resting Th2 and Trl T cells. The high expression of this transcript in secondary T cells treated with CD95 suggests that this transcript encodes for a protein involved in activation of cell death. Furthermore, high expression of the MOL5A transcript is also found in activated basophils and eosinophils, suggesting a role for this protein in allergic disorder such as asthma, contact hypersensitivity, and hypersensitive immediate reactions. Antibody or protein therapeutics designed against the protein encoded for by this transcript could therefore reduce or inhibit inflammation in allergy, asthma, emphysema, psoriasis and/or autoimmunity.

Panel CNSD.01 Summary: Agl215 Semaphorins can act as axon guidance proteins, specifically through their ability to act as chemorepellents that inhibit CNS regenerative capacity. Manipulation of levels ofthe MOL4 semaphorin-like protein may therefore be of use in inducing a compensatory synaptogenic response to neuronal death in Alzheimer's disease, Parkinson's disease, Huntington's disease, spinocerebellar ataxia, progressive supranuclear palsy, multiple sclerosis, ALS, head trauma, stroke, or any other disease/condition associated with neuronal loss.

F. MOL5d

Table BA. Probe Name: Agl215

Table BC. Panel 1.2

Table BD. Panel 2.2

Table BE. Panel 4D

Table BF. Panel 1.2

Table BG. Panel 4D

Table BH. Panel 1.4

Table Bl. Panel 3.2

Table BJ. Panel Hass

501

Example 2: TaqMan Data for MOL7

TaqMan data was acquired for MOL7 as described in Eaxample 1 using the primers specified. The relative expression of MOL7 in the described tissues is represented in the graphs below.

503

305 Example 3 SeqCallingTM Technology cDNA was derived from various human samples representing multiple tissue types, normal and diseased states, physiological states, and developmental states from different donors. Samples were obtained as whole tissue, cell lines, primary cells or tissue cultured primary cells and cell lines. Cells and cell lines may have been treated with biological or chemical agents that regulate gene expression for example, growth factors, chemokines, steroids. The cDNA thus derived was then sequenced using CuraGen's proprietary SeqCalling technology. Sequence traces were evaluated manually and edited for corrections if appropriate. cDNA sequences from all samples were assembled with themselves and with public ESTs using bioinformatics programs to generate CuraGen's human SeqCalling database of SeqCalling assemblies. Each assembly contains one or more overlapping cDNA sequences derived from one or more human samples. Fragments and ESTs were included as components for an assembly when the extent of identity with another component ofthe assembly was at least 95% over 50 bp. Each assembly can represent a gene and/or its variants such as splice forms and/or single nucleotide polymorphisms (SNPs) and their combinations.

Variant sequences are included in this application. A variant sequence can include a single nucleotide polymorphism (SNP). A SNP can, in some instances, be referred to as a "cSNP" to denote that the nucleotide sequence containing the SNP originates as a cDNA. A SNP can arise in several ways. For example, a SNP may be due to a substitution of one nucleotide for another at the polymorphic site. Such a substitution can be either a transition or a transversion. A SNP can also arise from a deletion of a nucleotide or an insertion of a nucleotide, relative to a reference allele. In this case, the polymorphic site is a site at which one allele bears a gap with respect to a particular nucleotide in another allele. SNPs occurring within genes may result in an alteration ofthe amino acid encoded by the gene at the position ofthe SNP. Intragenic SNPs may also be silent, however, in the case that a codon including a SNP encodes the same amino acid as a result ofthe redundancy ofthe genetic code. SNPs occurring outside the region of a gene, or in an intron within a gene, do not result in changes in any amino acid sequence of a protein but may result in altered regulation ofthe expression pattern for example, alteration in temporal expression, physiological response regulation, cell type expression regulation, intensity of expression, stability of transcribed message. Method of novel SNP Identification: SNPs are identified by analyzing sequence assemblies using CuraGen's proprietary SNPTool algorithm. SNPTool identifies variation in assemblies with the following criteria: SNPs are not analyzed within 10 base pairs on both ends of an alignment; Window size (number of bases in a view) is 10; The allowed number of mismatches in a window is 2; Minimum SNP base quality (PHRED score) is 23; Minimum number of changes to score an SNP is 2/assembly position. SNPTool analyzes the assembly and displays SNP positions, associated individual variant sequences in the assembly, the depth of the assembly at that given position, the putative assembly allele frequency, and the SNP sequence variation. Sequence traces are then selected and brought into view for manual validation. The consensus assembly sequence is imported into CuraTooIs along with variant sequence changes to identify potential amino acid changes resulting from the SNP sequence variation. Comprehensive SNP data analysis is then exported into the SNPCalling database.

Method of novel SNP Confirmation: SNPs are confirmed employing a validated method know as Pyrosequencing (Pyrosequencing, Westborough, MA). Detailed protocols for Pyrosequencing can be found in:

Alderborn et al. Determination of Single Nucleotide Polymorphisms by Real-time Pyrophosphate DNA Sequencing. (2000). Genome Research. 10, Issue 8, August. 1249- 1265. In brief, Pyrosequencing is a real time primer extension process of genotyping.

This protocol takes double-stranded, biotinylated PCR products from genomic DNA samples and binds them to streptavidin beads. These beads are then denatured producing single stranded bound DNA. SNPs are characterized utilizing a technique based on an indirect bioluminometric assay of pyrophosphate (PPi) that is released from each dNTP upon DNA chain elongation. Following Klenow polymerase-mediated base incorporation, PPi is released and used as a substrate, together with adenosine 5'-phosphosulfate (APS), for ATP sulfurylase, which results in the formation of ATP. Subsequently, the ATP accomplishes the conversion of luciferin to its oxi-derivative by the action of luciferase. The ensuing light output becomes proportional to the number of added bases, up to about four bases. To allow processivity of the method dNTP excess is degraded by apyrase, which is also present in the starting reaction mixture, so that only dNTPs are added to the template during the sequencing. The process has been fully automated and adapted to a 96-well format, which allows rapid screening of large SNP panels. Example 4 SAGE data

Serial Analysis of Gene Expression, or SAGE, is an experimental technique designed to gain a quantitative measure of gene expression. The SAGE technique itself includes several steps utilizing molecular biological, DNA sequencing and bioinformatics techniques. These steps (reviewed in Adams MD, "Serial analysis of gene expression:

ESTs get smaller." Bioessays. 18(4):261-2 (1996)) have been used to produce 9 or 10 base "tags", which are then, in some manner, assigned gene descriptions. For experimental reasons, these tags are immediately adjacent to the 3' end ofthe 3'-mostNlaIlI restriction site in cDNA sequences. The Cancer Genome Anatomy Project, or CGAP, is an NCI- initiated and sponsored project, which hopes to delineate the molecular fingerprint ofthe cancer cell. It has created a database of those cancer-related projects that used SAGE analysis in order to gain insight into the initiation and development of cancer in the human body. The SAGE expression profiles reported in this invention are generated by first identifying the Unigene accession ID associated with the given MTC gene by querying the Unigene database at http://www.ncbi.nlm.nih.gov/UniGene/. This page has then a link to the SAGE : Gene to Tag mapping (http://www.ncbi.nlm.nih.gov/SAGE/SAGEcid.cgi?cid="unigenelD").

This generated the reports that are included in this application, which list the number of tags found for the given gene in a given sample along with the relative expression. This information is then used to understand whether the gene has a more general role in tumorogenesis and/or tumor progression. A list ofthe SAGE libraries generated by CGAP and used in the analysis can be found at http://www.ncbi.nlm.nih.gov/SAGE/sagelb.cgi.

MOL4b

SAGE data

Hs 6138- : KIAA1445 rjrotein

SAGE library data and reliable tag summarr

Reliable tags found m SAGE libraries

Tagsper Tag

Li&rarr name million ratal tags

SAGE Duke 1273 51 <■*> 2 3SS36

SAGE Duke HI D_π 19 1 52371

SAGE ooolerl GBlJΪ 32 2 61841

SAGE Duke mhh-1 20 1 4S4S8

SAGE Meso-12 28 1 35032

SAGE Duke H247.ιormal 33 Λ* 2 60543

SAGE Duke H1043 26 2 7ι5673 NOV5d SAGE data

SAGE data

Example 5. Identification of NOVX clones

The novel target sequences identified in the present invention were subjected to the exon linking process to confirm the sequence. PCR primers were designed by starting at the most upstream sequence available, for the forward primer, and at the most downstream sequence available for the reverse primer. Table AAO shows the sequences ofthe PCR primers used for obtaining different clones. In each case, the sequence was examined, walking inward from the respective termini toward the coding sequence, until a suitable sequence that is either unique or highly selective was encountered, or,^' in the case ofthe reverse primer, until the stop codon was reached. Such primers were designed based on in silico predictions for the full length cDNA, part (one or more exons) ofthe DNA or protein sequence of he target sequence, or by translated homology ofthe predicted exons to closely related human sequences from other species. These primers were then employed in PCR amplification based on the following pool of human cDNAs: adrenal gland, bone marrow, brain - amygdala, brain - cerebellum, brain - hippocampus, brain - substantia nigra, brain - thalamus, brain -whole, fetal brain, fetal kidney, fetal liver, fetal lung, heart, kidney, lymphoma - Raji, mammary gland, pancreas, pituitary gland, placenta, prostate, salivary gland, skeletal muscle, small intestine, spinal cord, spleen, stomach, testis, thyroid, trachea, uterus. Usually the resulting amplicons were gel purified, cloned and sequenced to high redundancy. The PCR product derived from exon linking was cloned into the pCR2.1 vector from Invitrogen. The resulting bacterial clone has an insert covering the entire open reading frame cloned into the pCR2.1 vector. Table AAP shows a list of these bacterial clones. The resulting sequences from all clones were assembled with themselves, with other fragments in CuraGen Corporation's database and with public ESTs. Fragments and ESTs were included as components for an assembly when the extent of their identity with another component ofthe assembly was at least 95% over 50 bp. In addition, sequence traces were evaluated manually and edited for corrections if appropriate. These procedures provide the sequence reported herein.

Table AAO. PCR Primers for Exon Linking

Physical clone: Exons were predicted by homology and the intron/exon boundaries were determined using standard genetic rules. Exons were further selected and refined by means of similarity determination using multiple BLAST (for example, tBlastN, BlastX, and BlastN) searches, and, in some instances, GeneScan and Grail. Expressed sequences from both public and proprietary databases were also added when available to further define and complete the gene sequence. The DNA sequence was then manually corrected for apparent inconsistencies thereby obtaining the sequences encoding the full-length protein.

Table 11B. Physical Clones for PCR products

NOVX Clone Bacterial Clone

NOV1 Physical clone 128940: : 83420733.698715.E24

NOV2 Physical clone A 357059, AL022344, A 3555530, AL356100, AC016042

NOV4 Physical clone AC009785

NOV5 Genomic clone: GMChromosome4

NO 7a Genomic file: gb_AC010319 HTG Homo sapiens [ chromosome 19 CTD- 2521M24

NOV8 Physical clone AC008803, AC010449, AC026718

Example 6. Preparation of expression vector pCEP4/Sec

The oligonucleotide primers, pSec-V5-His Forward 5'-CTCGTCCTCG AGGGTAAGCC TATCC CTAAC-3' (SEQ ID NO: 178) and pSec-V5-His Reverse 5'- CTCGTCGGGC CCCTGATCAG CGGGTTTAAA C-3' (SEQ ID NO: 179), were designed to amplify a fragment from the pcDNA3.1-V5His (Invitrogen, Carlsbad, CA) expression vector. The PCR product was digested with Xhol and Apal and ligated into the Xhol/Apal digested pSecTag2 B vector harboring an Ig kappa leader sequence (Invitrogen, Carlsbad CA). The correct structure ofthe resulting vector, pSecV5His, was verified by DNA sequence analysis. The vector pSecV5His was digested with Pmel and Nhel, and the Pmel-Nhel fragment was ligated into the BamHI/Klenow and Nhel treated vector pCEP4 (Invitrogen, Carlsbad, CA). The resulting vector was named pCEP4/Sec. Example 7. Expression of hll753149 in human embryonic kidney 293 cells.

The Bglll-Xhol fragment containing the human clone 1 1753149 sequence was isolated from 1 1753149-pCR2.1 and subcloned into the vector pCEP4/Sec to generate expression vector pCEP4/Sec-l 1753149. The pCEP4/Sec-l 1753149 vector was transfected into 293 cells using LipofectaminePlus™ reagent (Life Technologies,

Rockville, MD) following the manufacturer's instructions. The cell pellet and supernatant were harvested 72 hours after transfection and examined for hi 1753149 expression by Western blotting (reducing conditions) with an anti-V5 antibody. Table AAQ shows that hi 1753149 is expressed as a protein secreted by 293 cells that is broadly distributed around 64 IdDa, with a minor band at 35 kDa. The predicted molecular weight ofthe cloned fragment of 1 1753149 is about 32 kDa. The low intensity band, observed at about 35 kDa in Table AAQ, corresponds closely to the predicted molecular weight ofthe unmodified gene product. The program PROSITE predicts seven potential N- glycosylation sites in this fragment. Variable glycosylation ofthe recombinant 1 1753149 protein would account for the broad distribution of protein observed around 64 kDa in Table AAQ

$*≠

Table AAQ. hi 1753149 protein secreted by 293 cells. Example 8. In-frame Cloning Clone 4437909

The expected 717 bp amplified product was detected by agarose gel electrophoresis. The fragment was purified from agarose gel and ligated to pCR2.1 vector (Invitrogen, Carlsbad, CA) following the manufacturer's recommendation. The cloned insert was sequenced using vector specific M13 Forward and M13 Reverse primers and the following gene-specific primers: 4437909 SI: 5'-GAGGACGGCTCCGTGAAC-3' (SEQ ID NO:180), 4437909 S2: 5'-GTTCACGGAGCCGTCCTC-3' (SEQ ID NO:181), 4437909 S3: 5'-CAGCGGCATGAGGTTCACC-3' (SEQ ID NO:182), and 4437909 S4: 5'-GGTGAACCTCATGCCGCTG-3' (SEQ ID NO:183).

Example 9. Expression of h4437909 in human embryonic kidney 293 cells.

The Bglll-Xhol fragment containing the human 4437909 sequence was isolated from plasmid 4437909-pCR2.1 and subcloned into the vector pCEP4/Sec to generate expression vector pCEP4/Sec-4437909. The pCEP4/Sec-4437909 vector was transfected into 293 cells using the LipofectaminePlus™ reagent following the manufacturer's instructions (Gibco BRL, Life Technologies, Inc., Rockville, MD).). The cell pellet and supernatant were harvested 72 hours after transfection and examined for h4437909 expression by Western blotting (reducing conditions) with an anti-V5 antibody. Table AAS shows that h4437909 is expressed in 293 cells as three discrete secreted protein bands of 16, 40, and 70 kDa. The predicted molecular weight is 27064 Da. There is one N- glycosylation site predicted at residue 118. Accordingly it is believed that the band at about 40 kDa corresponds to the full sized monomeric form of the protein encoded by pCEP4/Sec-4437909.

ssrk-ϊv - ϋϋ Table AAS. h4437909 protein secreted by 293 cells.

Example 10. Expression of h4437909 in recombinant E. coli cells using the expression vector pETMY- h4437909.

The vector pRSETA (InVitrogen Inc., Carlsbad, CA) was digested with Xhol and Ncol restriction enzymes. Oligonucleotide linkers used include Linker 1 : 5'- CATGGTCAGCCTAC-3' (SEQ ID NO: 184) and Linker 2: 5'-TCGAGTAGGCTGAC-3' (SEQ ID NO: 185). Linker 1 and Linker 2 were annealed at 37 degree Celsius and ligated into the Xhol-Ncol treated pRSETA. The resulting vector was confirmed by restriction analysis and sequencing and was named as pETMY. The Bgllll-Xhol fragment (see above) was ligated into the pETMY that was digested with BamHI and Xhol restriction enzymes. The expression vector is named as pETMY-4437909. In this vector, h4437909 was fused to the 6 X His tag and T7 epitope at its N-terminus. The plasmid pETMY- 4437909 was then transformed into the E. coli expression host BL21(DE3, pLys) (Novagen, Madison, WI). Expression of protein 4437909 was induced according to the manufacturer's instructions. After induction, total cells were harvested, and proteins were analyzed by Western blotting using anti-HisGly antibody (Invitrogen, Carlsbad, CA). FIG. 17 shows h4437909 was expressed as a 34 kDa protein in E. coli cells. This corresponds approximately to the molecular weight of 27064 Da expected for the protein encoded by pETMY-4437909.

Example 11. Quantitative expression analysis of 3883556 nucleic acid The quantitative expression of clone 3883556 was assessed in 41 normal and 55 tumor samples (see Table 2) by real time quantitative PCR (TAQMAN") performed on a Perkin-Elmer Biosystems ABI PRISM® 7700 Sequence Detection System.

First, 96 RNA samples were normalized to beta-actin and GAPDH. RNA (-50 ng total RNA or ~1 ng polyA+ RNA) was converted to cDNA using the TAQMAN^® Reverse Transcription Reagents Kit (PE Biosystems, Foster City, CA; cat # N808-0234) and random hexamers according to the manufacturer's protocol. Reactions were performed in 20 μl and incubated for 30 min. at 48°C. The cDNA (5 μl) was then transferred to a separate plate for the TAQMAN^® reaction using beta-actin and GAPDH TAQMAN® Assay Reagents (PE Biosystems; cat. #'s 4310881E and 4310884E, respectively) and TAQMAN® universal PCR Master Mix (PE Biosystems; cat # 4304447) according to the manufacturer's protocol. Reactions were performed in 25 μl using the following parameters: 2 min. at 50°C; 10 min. at 95°C; 15 sec. at 95°C/1 min. at 60°C (40 cycles). Results were recorded as CT values (cycle at which a given sample crosses a threshold level of fluorescence) using a log scale, with the difference in RNA concentration between two samples being represented as 2 to the power of delta CT (i.e., 2^ΔCT). The average CT values obtained for β-actin and GAPDH were used to normalize RNA samples. The RNA sample generating the highest CT value required no further diluting, while all other samples were diluted relative to this sample according to their beta-actin /GAPDH average CT values.

Normalized RNA (5 μl) was converted to cDNA and analyzed via TAQMAN^® using One Step RT-PCR Master Mix Reagents (PE Biosystems; cat. # 4309169) and gene- specific primers according to the manufacturer's instructions. Probes and primers were designed for each assay according to Perkin Elmer Biosystem's Primer Express Software package (version I for Apple Computer's Macintosh Power PC) using the sequence of 3352358 as input. The primers used were Ag 45 (F): 5'-TCCCTGGGAA ATGTCACACA-3' (SEQ ID NO: 186) and Ag 45 (R): 5'-TTCCTGGTGC CAAAGAATGA G-3' (SEQ ID NO: 187). and the labeled probe was Ag 45 (P): TET-5'- AGAACATCAA TCTTCCTTCC CCACTCCTGA G-3'-TAM (SEQ ID NO: 188).

Default settings were used for reaction conditions and the following parameters were sef before selecting primers: primer concentration = 250 nM, primer melting temperature (T_m) range = 58°-60° C, primer optimal Tm = 59° C, maximum primer difference = 2° C, probe does not have 5' G, probe T,_n must be 10° C greater than primer T_m, amplicon size = 75 bp to 100 bp. The probes and primers selected (see below) were synthesized by Synthegen (Houston, TX, USA). Probes were double FIPLC purified to remove uncoupled dye and evaluated by mass spectroscopy to verify coupling of reporter and quencher dyes to the 5' and 3' ends ofthe probe, respectively. The final concentrations for the forward and reverse primers were 900 nM each, and probe concentration was 200 nM.

PCR conditions: Normalized RNA from each tissue and each cell line was spotted in each well of a 96 well PCR plate (Perkin Elmer Biosystems). PCR cocktails including two probes (SEQX-specific and another gene-specific probe multiplexed with the SEQX probe) were set up using IX TaqMan™ PCR Master Mix for the PE Biosystems 7700, with 5 M MgCl₂, dNTPs (dA, G, C, U at 1:1 :1 :2 ratios), 0.25 U/ml AmpliTaq Gold™ (PE Biosystems), and 0.4 U/μl RNase inhibitor, and 0.25 U/μl reverse transcriptase. Reverse transcription was performed at 48° C for 30 minutes followed by PCR amplification cycles as follows: 95° C 10 min, then 40 cycles of 95° C for 15 seconds, 60° C for 1 minute.

The TaqMan panel is shown in Table AAU, Panels A, B and C. Tissues with high levels of expression include fetal brain, cerebellum, hippocampus, hypothalamus, liver, kidney, breast cancer, and uterus. These results suggest therapeutic indications for targeting 3883556 include brain tumors, preferably astrocytomas and gliomas; carcinomas such as selected renal cell and ovarian carcinomas.

Table AAT. Tissue Sources of RNA

Table AAU

Tissue Expression of 3883556 (A)

Tissue Source of RNA

Table AAV. TaqMan results for 3883556. Panel B. Relative Expression (%)

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Lung ca (small cell) NCI-H69

Lung ca (s cell var ) SHP-77

Lung ca (large cell)NCI-H460

Lung ca (non-s cl) NCI H522

Lung ca (squam ) ΞW900

Table AAW. TaqMan results for 3883556. Panel C.

Tissue Expression of 3883556 (C)

Tissue Source of RNA

Example 12. Quantitative expression analysis of 4324229 nucleic acids

The quantitative expression of clone 4324229 was assessed in normal and tumor by real time quantitative PCR (TAQMAN^®) as described in EXAMPLE 8. The 4324229 clone-specific primers used were AblO(F): 5'-GCCTGGCTCTCTGGATAGACA-3' (SEQ ID NO: 189) and Abl O(R): 5'-CACGAGCAGC TGTTCCAGAC-3' (SEQ ID NO: 190), and the labeled probe was Abl O(P):-FAM-5'-TGGCGGCACA TTCACCTGCA G-3'-TAMRA (SEQ ID NO: 191). The tissue sources are listed in Table AAT. The results are shown in Tables AAX-AAZ, Panels A, B and C. Among the tissues showing a high level of expression is lung (NCI-H460). The results suggest that therapeutic indications for targeting 4324229 include selected lung, breast and ovarian carcinomas. Table AAX. TaqMan results for 4324229. Panel A.

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Table AAY. TaqMan results for 4324229. Panel B.

Tissue Expression of 4324229 (B)

Tissue Source of RNA Table AAZ. TaqMan results for 4324229. Panel C.

Tissue Expression of 4324229 (C)

Tissue Source of RNA

Example 13. Quantitative expression analysis of 4339264 nucleic acid

The quantitative expression of clone 4339264 was assessed in normal and tumor by real time quantitative PCR (TAQMAN"⁵) as described in Example 8. The clone- specific primers used were Ag 120 (F): 5'-AAAGGCGGAGGAAAGAAGTACTC-3' (SEQ ID NO: 192) and Ag 120 (R): 5'-GCTCCCGTTC CCTCTCCA-3' (SEQ ID NO: 193), and the labeled probe was Ag 120 (P): FAM-5'-CCTCTTTGTT CTTCTTGCCC GAGTTTTCTT T-3'-TAMRA (SEQ ID NO: 194).

The tissue sources are listed in Table AAT. The results are shown in Table ABA- ABC, Panels A, B and C. The highest expression was shown in Prostate ca (bone met) PC- 3. Other tissues showing a high level expression include adipose, colon ca. (HCT-1 16), renal ca. ( A498), lung ca. (S. CELL var.) SHP-77, lung ca. (large cell) NCI-H460, ovary, testis and melanoma (LOX IMVI). Furthermore the results suggest that clone 4339264 is downregulated in astrocytoma, when compared with normal brain or glioma. Therefore restoring the expression of 4339264 could be useful for the treatment of astrocytomas. Since it is a multiple membrane spanning protein, some kind of gene therapy would be necessary. Table ABA. TaqMan results for 4339264. Panel A.

Table ABB. TaqMan results for 4339264. Panel B.

Relative Expression (%)

t

Table ABC. TaqMan results for 4339264. Panel C.

Example 14. Quantitative expression analysis of 4391184 nucleic acid.

The quantitative expression of clone 4391 184 was assessed in normal and tumor by real time quantitative PCR (TAQMAN^®) as described in Example 8. The clone- specific primers used were Abl 1 (F): 5'-TGGAAGTCCCTCGGTAAAGGA-3' (SEQ ID NO: 195) and Abl 1 (R): 5'-AGGACACCTG TGCCCTGTCT-3' (SEQ ID NO: 196), and the labeled probe was Abl 1 (P): FAM-5'-CCCGCCTTGC CATTCCCTTC A -3'- TAMRA (SEQ ID NO: 197).

The tissue sources are listed in Table AAT. The results are shown in Tables ABD- ABF, Panels (A), (B) and (C). The highest expression was shown in prostate ca. (bone met) PC-3. Other tissues showing a high level expression include adipose, colon ca. (HCT-116), renal ca. ( A498), lung ca. (S. CELL var.) SHP-77, lung ca. (large cell)NCI- H460, ovary, testis and melanoma (LOX IMVI). Furthermore the results suggest that clone 4391184 is downregulated in astrocytoma, when compared with normal brain or glioma. Therefore restoring the expression of 4339264 could be useful for the treatment of astrocytomas. Since it is a multiple membrane spanning protein, some kind of gene therapy would be necessary. Clone 4391184 is up-regulated in hematopoietic organs, bone marrow, thymus, spleen and lymph node, therefore it can have a hematopoietic activity, useful as protein drug after chemotherapy treatment. This exclude a systemic delivery of a targeting agent. If specific delivery could be achieved, targeting agent could be useful to treat breast tumors and selected melanomas.

Table ABD. TaqMan results for Tissue Expression of 4391184. Panel A.

Tissue Expression of 4391184 (A)

Table ABE. TaqMan results for Tissue Expression of 4391184. Panel B.

Table ABF. TaqMan results for Tissue Expression of 4391184. Panel C.

Tissue Expression of 4391184 (C)

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Example 15. Radiation Hybrid Mapping Identifies the Chromosomal Location of Clones of the Invention.

Radiation hybrid mapping using human chromosome markers was carried out for many ofthe clones described in the present invention. The procedure used to obtain these results is analogous to that described in Steen et al. (A High-Density Integrated Genetic Linkage and Radiation Hybrid Map ofthe Laboratory Rat, Genome Research 1999 (Published Online on May 21, 1999) Vol. 9, AP1-AP8, 1999). A panel of 93 cell clones containing the randomized radiation-induced human chromosomal fragments was screened in 96 well plates using PCR primers designed to identify the sought clones in a unique fashion. The results are presented in Table ABG, which provides four columns giving, respectively, the clone number, the chromosome on which the clone is found, the distance in cR from a marker gene to the sought clone, and the identity ofthe marker gene. Table ABG. Radiation Hybrid Mapping Results for Clones of the Invention

Example 16. Quantitative expression analysis of 4324229 nucleic acids

The quantitative expression of clone 4324229-02 was assessed in normal and tumor by real time quantitative PCR (TAQMAN^®) as described in EXAMPLE 1 1. The 4324229-02 clone-specific primers used were as follows:

Table ABH

The tissue sources are listed in Table AAT. The results are shown in FIG. 24. Among the tissues showing a high level of expression is, for example but not limited to lung (NCI-H460). The results suggest that therapeutic indications for targeting 4324229 include selected lung, breast, bladder and ovarian carcinomas. For example, therapeutic targeting with an antibody or domain thereof will block the migration and growth of cancer cells and promote cell death in cells where the gene is overexpressed in the tumor compared to normal adjacent tissues.

Table ABI. TaqMan results for Tissue Expression of 4324229-2. Panel A.

Panel E.

538

Panel G.

Example 16. Molecular Cloning of CG52643-02

Clone CG52643-02 encodes a follistatin-like protein, similar to clones AC012614J.0.123 and 4324229-2 described above, and has the same properties and uses described for these clones, i.e., regulation of cellular proliferation, cancers, and reproduction.

Exon Linking: The cDNA coding for the full-length of CG52643-02 from residue 1 to 842 and 23-842 were targeted for "in-frame" cloning by PCR. The PCR template is based on the previously identified plasmid, when available, or on human cDNA(s).

Table ABJ

For downstream cloning purposes, the forward primer includes an in-frame Xho I restriction site and the reverse primer contains an in-frame Xho I restriction site. Two parallel PCR reactions were set up using a total of 0.5-1.0 ng human pooled cDNAs as template for each reaction. The pool is composed of 5 micrograms of each ofthe following human tissue cDNAs: adrenal gland, whole brain, amygdala, cerebellum, thalamus, bone marrow, fetal brain, fetal kidney, fetal liver, fetal lung, heart, kidney, liver, lymphoma, Burkitt's Raji cell line, mammary gland, pancreas, pituitary gland, placenta, prostate, salivary gland, skeletal muscle, small Intestine, spleen, stomach, thyroid, trachea, uterus. When the tissue of expression is known and available, the second PCR was performed using the above primers and 0.5ng-1.0 ng of one ofthe following human tissue cDNAs: skeleton muscle, testis, mammary gland, adrenal gland, ovary, colon, normal cerebellum, normal adipose, normal skin, bone marrow, brain amygdala, brain hippocampus, brain substantia nigra, brain thalamus, thyroid, fetal lung, fetal liver, fetal brain, kidney, heart, spleen, uterus, pituitary gland, lymph node, salivary gland, small intestine, prostate, placenta, spinal cord, peripheral blood, trachea, stomach, pancreas, hypothalamus. The reaction mixtures contained 2 microliters of each ofthe primers (original concentration: 5 pmol/ul), 1 microliter of lOmM dNTP (Clontech Laboratories, Palo Alto CA) and 1 microliter of Pfu DNA polymerase (Strategene) in 50 microliter- reaction volume. The following reaction conditions were used: PCR condition 1 : a) 96°C 3 minutes b) 96°C 30 seconds denaturation c) 60°C 30 seconds, primer annealing d) 72°C 6 minutes extension Repeat steps b-d 15 times e) 96°C 15 seconds denaturation f) 60°C 30 seconds, primer annealing g) 72°C 6 minutes extension Repeat steps e-g 29 times e) 72°C 10 minutes final extension

PCR condition 2: a) 96°C 3 minutes b) 96°C 15 seconds denaturation c) 76°C 30 seconds, reducing the temperature by 1 °C per cycle d) 72°C 4 minutes extension Repeat steps b-d 34 times e) 72°C 10 minutes final extension.

An amplified product was detected by agarose gel electrophoresis. The fragment was gel-purified and ligated into the pCR2.1-TOPO vector (Invitrogen, Carlsbad, CA) following the manufacturer's recommendation. Twelve clones per PCR reaction were picked and sequenced. The inserts were sequenced using vector-specific M13 Forward and Ml 3 Reverse primers and the following gene-specific primers for assembly ^• 259341359:

Table ABK

The insert assembly 259341359 shown at Table ABM was found to encode an open reading frame between residues 1 and 842 ofthe target sequence of CG52643-02, shown at Table ABL The cloned insert is 100% identical to the original sequence. A comparison ofthe polypeptide sequences of CG52643-02 and 259341359 is shown at Table ABN.

Table ABL DNA Sequence of CG52643-02 (SEQ ID NO:228)

GGAGAGGGCTGCATTGCTGTTGCTCACTGACCTTCTTTTATGCTGGCCTTTGGTTCAGAATGGCACATCA TTCCTCGTTTTTGGCCCTCCAGCTGAACACCTGTTCTCTGTGGCACTGACTCCTCTTTCCATAGGGACAT CATACAACAGTCGCCTTTATCTGAGGTTGTGCAAAGAGGGATGGAGGAGAAAACAATGGAGAATCCCTGG

CAGATTTCCCCAGGACGAGAGAAGGATATCCAATTGCTCATCAGGGAAGGTGCTAGGTCTCCCAGCCAGA CGCCCTCAGAGGCCGGTGTCAAGTCTCCCTCACCTCTGTGATGTGAAGTCAGCTCGTTCATGACCTGGGC AGGCAGAGGGTCAGAGGGGCAGATGGAGCACTCCTGGCCTGATGAAGACTCATCAAAATGAAACCAGGAG GCTTTTGGCTGCATCTCACACTGCTCGGAGCCTCCCTGCCGGCTGCGCTGGGATGGATGGACCCAGGAAC CAGCAGAGGCCCGGATGTGGGTGTGGGGGAGTCACAGGCAGAGGAGCCCAGAAGCTTTGAAGTCACAAGA

AGAGAAGGGCTTTCCAGCCACAACGAGCTGCTGGCCTCCTGCGGGAAGAAGTTCTGCAGCCGAGGGAGCC GGTGCGTGCTCAGCAGGAAGACAGGGGAGCCCGAATGCCAGTGCCTGGAGGCATGCAGGCCCAGCTACGT GCCTGTGTGCGGCTCTGATGGGAGGTTTTATGAAAACCACTGTAAGCTCCACCGTGCTGCTTGCCTCCTG GGAAAGAGGATCACCGTCATCCACAGCAAGGACTGTTTCCTCAAAGGTGACACGTGCACCATGGCCGGCT ACGCCCGCTTGAAGAATGTCCTTCTGGCACTCCAGACCCGTCTGCAGCCACTCCAAGAAGGAGACAGCAG

ACAAGACCCTGCCTCCCAGAAGCGCCTCCTGGTGGAATCTCTGTTCAGGGACTTAGATGCAGATGGCAAT GGCCACCTCAGCAGCTCCGAACTGGCTCAGCATGTGCTGAAGAAGCAGGACCTGGATGAAGACTTACTTG GTTGCTCACCAGGTGACCTCCTCCGATTTGACGATTACAACAGTGACAGCTCCCTGACCCTCCGCGAGTT CTACATGGCCTTCCAAGTGGTTCAGCTCAGCCTCGCCCCCGAGGACAGGGTCAGTGTGACCACAGTGACC GTGGGGCTGAGCACAGTGCTGACCTGCGCCGTCCATGGAGACCTGAGGCCACCAATCATCTGGAAGCGCA

ACGGGCTCACCCTGAACTTCCTGGACTTGGAAGACATCAATGACTTTGGAGAGGATGATTCCCTGTACAT CACCAAGGTGACCACCATCCACATGGGCAATTACACCTGCCATGCTTCCGGCCACGAGCAGCTGTTCCAG ACCCACGTCCTGCAGGTGAATGTGCCGCCAGTCATCCGTGTCTATCCAGAGAGCCAGGCACAGGAGCCTG GAGTGGCAGCCAGCCTAAGATGCCATGCTGAGGGCATTCCCATGCCCAGAATCACTTGGCTGAAAAACGG CGTGGATGTCTCAACTCAGATGTCCAAACAGCTCTCCCTTTTAGCCAATGGGAGCGAACTCCACATCAGC

AGTGTTCGGTATGAAGACACAGGGGCATACACCTGCATTGCCAAAAATGAAGTGGGTGTGGATGAAGATA TCTCCTCGCTCTTCATTGAAGACTCAGCTAGAAAGACCCTTGCAAACATCCTGTGGCGAGAGGAAGGCCT CAGCGTGGGAAACATGTTCTATGTCTTCTCCGACGACGGTATCATCGTCATCCATCCTGTGGACTGTGAG ATCCAGAGGCACCTCAAACCCACGGAAAAGATTTTCATGAGCTATGAAGAAATCTGTCCTCAAAGAGAAA AAAATGCAACCCAGCCCTGCCAGTGGGTATCTGCAGTCAATGTCCGGAACCGGTACATCTATGTGGCCCA

GCCAGCACTGAGCAGAGTCCTTGTGGTCGACATCCAAGCCCAGAAAGTCCTACAGTCCATAGGTGTGGAC CCTCTGCCGGCTAAGCTGTCCTATGACAAGTCACATGACCAAGTGTGGGTCCTGAGCTGGGGGGACGTGC ACAAGTCCCGACCAAGTCTCCAGGTGATCACAGAAGCCAGCACCGGCCAGAGCCAGCACCTCATCCGCAC ACCCTTTGCAGGAGTGGATGATTTCTTCATTCCCCCAACAAACCTCATCATCAACCACATCAGGTTTGGC TTCATCTTCAACAAGTCTGATCCTGCAGTCCACAAGGTGGACCTGGAAACAATGATGCCCCTCAAGACCA

TCGGCCTGCACCACCATGGCTGCGTGCCCCAGGCCATGGCACACACCCACCTGGGCGGCTACTTCTTCAT CCAGTGCCGACAGGACAGCCCCGCCTCTGCTGCCCGACAGCTGCTCGTTGACAGTGTCACAGACTCTGTG CTTGGCCCCAATGGTGATGTAACAGGCACCCCACACACATCCCCCGACGGGCGCTTCATAGTCAGTGCTG CAGCTGACAGCCCCTGGCTGCACGTGCAGGAGATCACAGTGCGGGGCGAGATCCAGACCCTGTATGACCT GCAAATAAACTCGGGCATCTCAGACTTGGCCTTCCAGCGCTCCTTCACTGAAAGCAATCAATACAACATC

TACGCGGCTCTGCACACGGAGCCGGACCTGCTGTTCCTGGAGCTGTCCACGGGGAAGGTGGGCATGCTGA AGAACTTAAAGGAGCCACCCGCAGGGCCAGCTCAGCCCTGGGGGGGTACCCACAGAATCATGAGGGACAG TGGGCTGTTTGGACAGTACCTCCTCACACCAGCCCGAGAGTCACTGTTCCTCATCAATGGGAGACAAAAC ACGCTGCGGTGTGAGGTGTCAGGTATAAAGGGGGGGACCACAGTGGTGTGGGTGGGTGAGGTATGAAGGG CCCAGAGCAGAGCCCTGGGCCAAGGAACACCCCCTAGTCCTGACACTGCAGCCTCAAGCAGGTACGCTGT ACATTTTTACAGACAAAAGCAAAAACCTGTACTCGCTTTGTGGTTCAACACTGGTCTCCTTGCAAGTTTC CTAGTATAAGGTATGCGCTGCTACCAAGATTGGGGTTTTTTCGTTAGGAAGTATGATTTATGCCTTGAGC TACGATGAGAACATATGCTGCTGTGTAAAGGGATCATTTCTGTGCCAAGCTGCACACCGAGTGACCTGGG

GACATCATGGAACCAAGGGATCCTGCTCTCCAAGCAGACACCTCTGTCAGTTGCCTTCACATAGTCATTG TCCCTTACTGCCAGACCCAGCCAGACTTTGCCCTGACGGAGTGGCCCGGAAGCAGAGGCCGACCAGGAGC AGGGGCCTCCCTCCCGAACTGAAAGCCCATCCGTCCTCGCGTGGGACCGCATCTTCTCCCTCGCAGCTGC TTCTTGCTTTTCTTTCCATTTGACTTGCTGTAAGCCTGAGGGAGAGCCAACAAGACTTACTGCATCTTGG GGGATGGGGAAATCACTCACTTTATTTTGGAAATTTTTGATTAAAAAAAAATTTTATAATCTCAAATGCT

AGTAAGCAGAAAGATGCTCTCCGAGGTCCAACTATATCCTTCCCTGCCTTAGGCCGAGTCTCGGGGGTGG TCACAACCCCACATCCCACAGCCAGAAAGAACAATGGTCATCTGAGAATACTGGCCCTGTCGACTATTGC CACCCTGCTTCTCCAAGAGCAGACCAGGCCACCTCATCCGTAAGGACTCGGTTCTGTGTTGGGACCCCAA AAAACCAGAACAAGTTCTGTGTGCCTCCTTTCAGCACAGAAGGGAGACATCTCATTAGTCAGGTCTGGTA CCCCAGATTCAGGGCAGACTGGGCTTGCCTGGCAAGGTATGGGTGGCCTCCAGGCTCAATGCAGAAACCC

CAAGGACACGAGTGGGGCCAGGTGAGTTCCTGAAGCTATACCTTTTCAAAACAGATTTTGTTTTCCTACC TGTGGCCCATCCACTCCTCTCTGGTACCCCATCCCCGCATCAGCACTGCAGAGAGAACACATTTCGGCGA GGGTTTTCTTACCCACATTCCCCAATCAATACACACACACTGCAGAACCCAGAACAGAAGGCCACAGGCT GGCACTACTGCATTCTCCTTATGTGTCTCAGGCTGTGGTGACTCTCACATGGGCATCGAAGAAGTACAAC CCACATAGCCCTCTGGAGACCGCCTAGATCAGAGACTCAGCAAAAACAGGCTCGCCTTCCCTCTCCCACA

TATGAGTGGAACTTACATGTGTCCTGGTTTGAATGATCATTTTGCAAGCCACACGGGTTGGGAGAGGTGG TCTCACCACAGACGTCTTTGCTAATTTGGCCACCTTCACCTACTGACATGACCAGGATTTTCCTTTGCCA TTAAGGAATGAACTCTTTCAAGGAGAGGAAACCCTAGACTCTGTGTCACTCTCAACACACACAGCTCCTT TCACTCCTGCCTGACTGCCAAGCCACCTGCATCCCCCGCCCCAGATCTCATGAGATCAATCACTTGTATG TCTCACGCAACTTGGTCCACCAAACGCCTGTCCCCTGTAACTCCTAGGGGTGCGCCTAGACAGGTACGTC

TGTTTTTTATTTTAAAAGATATGCTATGTAGATATAAGTTGAGGAAGCTCACCTCAAAAGCCTAGAATGC AGTTTCACAGTAGCTGGGATGCATGGATGACCCATCTCACCCCTTTTTTTTTCCTGCCTCAATATCTTGA TATGTTATGTTTACTCCCAATCTCCCATTTTTACCACTAAAATTCTCCAACTTTCATAAACTTTTTTTTG GAAAAATTTCCATTGTATCAGCCCCTGACAGAAAAAGGATCTCTGAGCCTAAAGGAGGAAAAGTCCCACC AACTACCAGACCAGAACACGAGCCCCTCTGGGCAGCAGGATTCCTAAGTCAAAGACCAGTTTGACCCAAA

CTGGCCTTTTAAAATAATCAGGAGTGACAGAGTCAACTTCTGCAGCACCTGCTTCTCCCCCACTGTCCCT TCCATCTTGGAATGTGTCTAAAAAAGCATAGCTGCCCTTTGCTGTCCTCAGAGTGCATTTCCTGGAGACG GCAGGCTTAGGTCTCACTGACAGCATGCCAGACACAACTGAATCGAAGCAGGCCTGAAGCCTAGGTCAGG GTTTCAGGAGTCCAGCCCCAGGAGGCAAAGTCACCAATGCAGGGAGGTAAATGCCTTTTGGCAGGAAAAC CAATAGAGTTGGTTGGGTGGGGAGTCAGGGGTGGGAGGAGAAGGAGGAAGAGGAGGAAGGCCAGACTGGC

CTGCCCTTTCTCCCATACTTCAeCCCAGCAGAGGTTCATGGGACACAGTTGGAAAGCCACTGGGAGGAAA TGCCTCACTACAGGGGGGCCTCCTGTAGCAAGCCCAGCCGGTAATCCTCCTAATGAACCCACAAGGTCAA TTCACAACTGATATCTTAGCTATTAAAGAAGTACTGACTTTACCAAAAGAATCATCAAGAAAGCTAT TA TATAAACCCCCTCAGTCATTTTGAAATAAAAXTAATTTTACAA

Table ABM DNA sequence of assembly 259341359 (SEQ ID NO:229)

CTCGAGATGAAACCAGGAGGCTTTTGGCTGCATCTCACACTGCTCGGAGCCTCCCTGCCGGCTGCGCTGG GATGGATGGACCCAGGAACCAGCAGAGGCCCGGATGTGGGTGTGGGGGAGTCACAGGCAGAGGAGCCCAG AAGCTTTGAAGTCACAAGAAGAGAAGGGCTTTCCAGCCACAACGAGCTGCTGGCCTCCTGCGGGAAGAAG

TTCTGCAGCCGAGGGAGCCGGTGCGTGCTCAGCAGGAAGACAGGGGAGCCCGAATGCCAGTGCCTGGAGG CATGCAGGCCCAGCTACGTGCCTGTGTGCGGCTCTGATGGGAGGTTTTATGAAAACCACTGTAAGCTCCA CCGTGCTGCTTGCCTCCTGGGAAAGAGGATCACCGTCATCCACAGCAAGGACTGTTTCCTCAAAGGTGAC ACGTGCACCATGGCCGGCTACGCCCGCTTGAAGAATGTCCTTCTGGCACTCCAGACCCGTCTGCAGCCAC TCCAAGAAGGAGACAGCAGACAAGACCCTGCCTCCCAGAAGCGCCTCCTGGTGGAATCTCTGTTCAGGGA CTTAGATGCAGATGGCAATGGCCACCTCAGCAGCTCCGAACTGGCTCAGCATGTGCTGAAGAAGCAGGAC CTGGATGAAGACTTACTTGGTTGCTCACCAGGTGACCTCCTCCGATTTGACGATTACAACAGTGACAGCT CCCTGACCCTCCGCGAGTTCTACATGGCCTTCCAAGTGGTTCAGCTCAGCCTCGCCCCCGAGGACAGGGT CAGTGTGACCACAGTGACCGTGGGGCTGAGCACAGTGCTGACCTGCGCCGTCCATGGAGACCTGAGGCCA CCAATCATCTGGAAGCGCAACGGGCTCACCCTGAACTTCCTGGACTTGGAAGACATCAATGACTTTGGAG

AGGATGATTCCCTGTACATCACCAAGGTGACCACCATCCACATGGGCAATTACACCTGCCATGCTTCCGG CCACGAGCAGCTGTTCCAGACCCACGTCCTGCAGGTGAATGTGCCGCCAGTCATCCGTGTCTATCCAGAG AGCCAGGCACAGGAGCCTGGAGTGGCAGCCAGCCTAAGATGCCATGCTGAGGGCATTCCCATGCCCAGAA TCACTTGGCTGAAAAACGGCGTGGATGTCTCAACTCAGATGTCCAAACAGCTCTCCCTTTTAGCCAATGG GAGCGAACTCCACATCAGCAGTGTTCGGTATGAAGACACAGGGGCATACACCTGCATTGCCAAAAATGAA

GTGGGTGTGGATGAAGATATCTCCTCGCTCTTCATTGAAGACTCAGCTAGAAAGACCCTTGCAAACATCC TGTGGCGAGAGGAAGGCCTCAGCGTGGGAAACATGTTCTATGTCTTCTCCGACGACGGTATCATCGTCAT CCATCCTGTGGACTGTGAGATCCAGAGGCACCTCAAACCCACGGAAAAGATTTTCATGAGCTATGAAGAA ATCTGTCCTCAAAGAGAAAAAAATGCAACCCAGCCCTGCCAGTGGGTATCTGCAGTCAATGTCCGGAACC GGTACATCTATGTGGCCCAGCCAGCACTGAGCAGAGTCCTTGTGGTCGACATCCAAGCCCAGAAAGTCCT

ACAGTCCATAGGTGTGGACCCTCTGCCGGCTAAGCTGTCCTATGACAAGTCACATGACCAAGTGTGGGTC CTGAGCTGGGGGGACGTGCACAAGTCCCGACCAAGTCTCCAGGTGATCACAGAAGCCAGCACCGGCCAGA GCCAGCACCTCATCCGCACACCCTTTGCAGGAGTGGATGATTTCTTCATTCCCCCAACAAACCTCATCAT CAACCACATCAGGTTTGGCTTCATCTTCAACAAGTCTGATCCTGCAGTCCACAAGGTGGACCTGGAAACA ATGATGCCCCTCAAGACCATCGGCCTGCACCACCATGGCTGCGTGCCCCAGGCCATGGCACACACCCACC

TGGGCGGCTACTTCTTCATCCAGTGCCGACAGGACAGCCCCGCCTCTGCTGCCCGACAGCTGCTCGTTGA CAGTGTCACAGACTCTGTGCTTGGCCCCAATGGTGATGTAACAGGCACCCCACACACATCCCCCGACGGG CGCTTCATAGTCAGTGCTGCAGCTGACAGCCCCTGGCTGCACGTGCAGGAGATCACAGTGCGGGGCGAGA TCCAGACCCTGTATGACCTGCAAATAAACTCGGGCATCTCAGACTTGGCCTTCCAGCGCTCCTTCACTGA AAGCAATCAATACAACATCTACGCGGCTCTGCACACGGAGCCGGACCTGCTGTTCCTGGAGCTGTCCACG

GGGAAGGTGGGCATGCTGAAGAACTTAAAGGAGCCACCCGCAGGGCCAGCTCAGCCCTGGGGGGGTACCC ACAGAATCATGAGGGACAGTGGGCTGTTTGGACAGTACCTCCTCACACCAGCCCGAGAGTCACTGTTCCT CATCAATGGGAGACAAAACACGCTGCGGTGTGAGGTGTCAGGTATAAAGGGGGGGACCACAGTGGTGTGG GTGGGTGAGGTACTCGAG

Table ABN. Comparison ofthe Polypeptide Sequences of CG52643-02 (SEQ ID NO:230) and 259341359 (SEQ ID NO:231).

Multiple Alignment:

CG52643-02 •κ*xtiti_vs_ :»ιt_*i(tr mn_'XΛ tw,HM_*_;itrΛt_ιiti-itrJM^ 259341359 60

CG52643-02 59 B ELLAS CGKKFCSRGSRCVLSRKTGEPECQCLEACRFSYVPVCGSDGRFYENHC LHRAi 118 259341359 61 B ELLAS CGKKFCSRGSRCVLSRKTGEPECOCLEACRFSYVPVCGSDGRFYENH.KLHRAi 120

--52643-02 119 LLGKRITV IHSKDCFLKGDTCTMAGYARLKNVLLALQTRLQPLQEGDSRQDPASQKRL 178 259341359 121 LLGKRITV I HS DCFLKGDTCTMAGYARLKNVLLALQTRLQFLQEGDSRQDPASQKRL1 180

CG52643-02 RDLDADGNGHLSS S ELAQH V LKKQDLDEDLLGCSFGDL LRFDD YNSDSS LTLRE 238 259341359 'ESLFRDLDADGNGHLSSS ELAQH VLKKODLDEDLLGCSPGDLLRFDD YNSDSS LTLREF

CG52643-02 239 IVVQ S AFEDRVS VTTVT V G L S TVLT CAVHGDLRPF I IWKRNGLTLNFLDLEDI N 259341359 241 'MAFQVVQLSLAPEDRVS VTTVT V GL S TVLT CAVHGDLRPF I I KRNGLTLNFLDLEDI N

CG52643-02 »r_wi<teiw-mt _________________t _____* _——____——v_9 _ 358 259341359 9 as m_Ψt_ WMmι ssϊaϊfXimmm_* _π^iiτ>__9tϊ ?i ιmn3_s_'a 360

CG52643-02 i a -i*- ___*__! ■ nSfi_!ilil___IAUriαιM«S__ l_R 418 259341359 ιιιaw;ιaiMwaffli;ιr<_ιt_<ιιι«gt«--i_t_κ_ιg»iMtat<»ιiMwιii8(^ 420

CG52643-02 GVDEDISS LF I EDSA R T LAN I LWREEGLS VGNMFYVFSDDGI I VIHP VDC E I QRHLKP 473 259341359 GVDEDISS FIEDSARKTLA I LWREEGLS VGNMFYVFSDDGI I VIHP VDCE I ORHLKP 4S0

CG52643-02 479 JPQREKNATQPCQWVSAVNV NRYIYVAQFALSRVLVVDIQAQKVLQS I 538 259341359 481 'EKIFMSYEE I CPQREKNATQPCQWVSAVNVRNR I VAQPALSRVL VDIQAOKVLOS I 543

CG52643-02 539 _* ι]'JIIVAMI-».β»a:ii-allAV_⁾Jll^^ι3αt>!lc«t:l_K|ia r*iTO(t»-«ti:.iH;**ra^,.tt_-tii]-;j 598 259341359 541 VDPLPA LS YDKSHDOV VLSWGDVHKSRPSLOVITEASTGQSOHLIRTPFAGVDDFFI 600

CG52643-02 I INHI RFGFI F NKSDPAVH KVDLETMMPLKTIGLHHHGCVPQAMAHTHLGGYFF I 658 259341359 PPTNLI INHI RFGFI F NK SDPAV H KVDLETM PLKTIGLHHHGCVPQAMAHTHLGGYFF I 660

CG52643-02 659 Λ*a«n _τ iWΛ;miMM*j w*aΛ Λt__tιιm rt__ai_Mm*itia&t β x Λ«! naviwit-wai 718 259341359 661 720

CG52643-02 719 Ii ;GEIQTLYDLQINSGI SD AFQRS FTESNQYNIYAALHTEPDLLFLELSTGKVGMLKNLK 778 259341359 721 ϋ LGEIQTLYDL INSGI S D LAFQR S F T ESNQYN I YAALHTEPDL LFLELSTGKVGMLKNLK 780

CG52643-02 EFFAGFAQPWGGTHRIMRDSGLFGQYLLTPARESLFLINGRQNTLR-EVSGIKGGTTVVW 838 259341359 EPPAGPAQPWGGTHRIMRDSGLFGQYLLTPARESLFLINGRQNTLRCEVSGIKGGTTVVW 840

CG52643-02 839 842 259341359 841 . 846

Table ABT. DNA sequence of assembly 268824728 (SEQ ID NO:232)

CTCGAGATGAAACCAGGAGGCTTTTGGCTGCATCTCACACTGCTCGGAGCCTCCCTGCCGGCTGCGCTGG GATGGATGGACCCAGGAACCAGCAGAGGCCCGGATGTGGGTGTGGGGGAGTCACAGGCAGAGGAGCCCAG

AAGCTTTGAAGTCACAAGAAGAGAAGGGCTTTCCAGCCACAACGAGCTGCTGGCCTCCTGCGGGAAGAAG TTCTGCAGCCGAGGGAGCCGGTGCGTGCTCAGCAGGAAGACAGGGGAGCCCGAATGCCAGTGCCTGGAGG CATGCAGGCCCAGCTACGTGCCTGTGTGCGGCTCTGATGGGAGGTTTTATGAAAACCACTGTAAGCTCCA CCGTGCTGCTTGCCTCCTGGGAAAGAGGATCACCGTCATCCACAGCAAGGACTGTTTCCTCAAAGGTGAC ACGTGCACCATTGCCGGCTACGCCCGCTTGAAGAATGTCCTTCTGGCACTCCAGACCCGTCTGCAGCCAC

TCCAAGAAGGAGACAGCAGACAAGACCCTGCCTCCCAGAAGCGCCTCCTGGTGGAATCTCTGTTCAGGGA CTTAGATGCAGATGGCAATGGCCACCTCAGCAGCTCCGAACTGGCTCAGCATGTGCTGAAGAAGCAGGAC CTGGATGAAGACTTACTTGGTTGCTCACCAGGTGACCTCCTCCGATTTGACGATTACAACAGTGACAGCT CCCTGACCCTCCGCGAGTTCTACATGGCCTTCCAAGTGGTTCAGCTCAGCCTCGCCCCCGAGGACAGGGT CAGTGTGACCACAGTGACCGTGGGGCTGAGCACAGTGCTGACCTGCGCCGTCCATGGAGACCTGAGGCCA

CCAATCATCTGGAAGCGCAACGGGCTCACCCTGAACTTCCTGGACTTGGAAGACATCAATGACTTTGGAG AGGATGATTCCCTGTACATCACCAAGGTGACCACCATCCACATGGGCAATTACACCTGCCATGCTTCCGG CCACGAGCAGCTGTTCCAGACCCACGTCCTGCAGGTGAATGTGCCGCCAGTCATCCGTGTCTATCCAGAG AGCCAGGCACAGGAGCCTGGAGTGGCAGCCAGCCTAAGATGCCATGCTGAGGGCATTCCCATGCCCAGAA TCACTTGGCTGAAAAACGGCGTGGATGTCTCAACTCAGATGTCCAAACAGCTCTCCCTTTTAGCCAATGG

GAGCGAACTCCACATCAGCAGTGTXCGGTATGAAGACACAGGGGCATACACCTGCATTGCCAAAAATGAA GTGGGTGTGGATGAAGATATCTCCTCGCTCTTCATTGAAGACTCAGCTAGAAAGACCCGCCTCAGCGTGG GAAACATGTTCTATGTCTTCTCCGACGACGGTATCATCGTCATCCATCCTGTGGACTGTGAGATCCAGAG GCACCTCAAACCCACGGAAAAGATTTTCATGAGCTATGAAGAAATCTGTCCTCAAAGAGAAAAAAATGCA ACCCAGCCCTGCCAGTGGGTATCTGCAGTCAATGTCCGGAACCGGTACATCTATGTGGCCCAGCCAGCAC

TGAGCAGAGTCCTTGTGGTCGACATCCAAGCCCAGAAAGTCCTACAGTCCATAGGTGTGGACCCTCTGCC GGCTAAGCTGTCCTATGACAAGTCACATGACCAAGTGTGGGTCCTGAGCTGGGGGGACGTGCACAAGTCC CGACCAAGTCTCCAGGTGATCACAGAAGCCAGCACCGGCCAGAGCCAGCACCTCATCCGCACACCCTTTG CAGGAGTGGATGATTTCTTCATTCCCCCAACAAACCTCATCATCAACCACATCAGGTTTGGCTTCATCTT CAACAAGTCTGATCCTGCAGTCCACAAGGTGGACCTGGAAACAATGATGCCCCTCAAGACCATCGGCCTG

CACCACCATGGCTGCGTGCCCCAGGCCATGGCACACACCCACCTGGGCGGCTACTTCTTCATCCAGTGCC GACAGGACAGCCCCGCCTCTGCTGCCCGACAGCTGCTCGTTGACAGTGTCACAGACTCTGTGCTTGGCCC CAATGGTGATGTAACAGGCACCCCACACACATCCCCCGACGGGCGCTTCATAGTCAGTGCTGCAGCTGAC AGCCCCTGGCTGCACGTGCAGGAGATCACAGTGCGGGGCGAGATCCAGACCCTGTATGACCTGCAAATAA ACTCGGGCATCTCAGACTTGGCCTTCCAGCGCTCCTTCACTGAAAGCAATCAATACAACATCTACGCGGC

TCTGCACATGGAGCCGGACCTGCTGTTCCTGGAGCTGTCCACGGGGAAGGTGGGCATGCTGAAGAACTTA AAGGAGCCACCCGCAGGGCCAGCTCAGCCCTGGGGGGGTACCCACAGAATCATGAGGGACAGTGGGCTGT TTGGACAGTACCTCCTCACACCAGCCCGAGAGTCACTGTTCCTCATCAATGGGAGACAAAACACGCTGCG GTGTGAGGTGTCAGGTATAAAGGGGGGGACCACAGTGGTGTGGGTGGGTGAGGTACTCGAG

Table ABU. DNA sequence of assembly 268825987 (SEQ ID NO:233)

CTCGAGATGAAACCAGGAGGCTTTTGGCTGCATCTCACACTGCTCGGAGCCTCCCTGCCGGCTGCGCTGG GATGGATGGACCCAGGAACCAGCAGAGGCCCGGATGTGGGTGTGGGGGAGTCACAGGCAGAGGAGCCCAG AAGCTTTGAAGTCACAAGAAGAGAAGGGCTTTCCAGCCACAACGAGCTGCTGGCCTCCTGCGGGAAGAAG

TTCTGCAGCCGAGGGAGCCGGTGCGTGCTCAGCAGGAAGACAGGGGAGCCCGAATGCCTGGGAAAGAGGA TCACCGTCATCCACAGCAAGGACTGTTTCCTCAAAGGTGACACGTGCACCATGGCCGGCTACGCCCGCTT GAAGAATGTCCTTCTGGCACTCCAGACCCGTCTGCAGCCACTCCAAGAAGGAGACAGCAGACAAGACCCT GCCTCCCAGAAGCGCCTCCTGGTGGAATCTCTGTTCAGGGACTTAGATGCAGATGGCAATGGCCACCTCA GCAGCTCCGAACTGGCTCAGCATGTGCTGAAGAAGCAGGACCTGGATGAAGACTTACTTGGTTGCTCACC AGGTGACCTCCTCCGATTTGACGATTACAACAGTGACAGCTCCCTGACCCTCCGCGAGTTCTACATGGCC TTCCAAGTGGTTCAGCTCAGCCTCGCCCCCGAGGACAGGGTCAGTGTGACCACAGTGACCGTGGGGCTGA GCACAGTGCTGACCTGCGCCGTCCATGGAGACCTGAGGCCACCAATCATCTGGAAGCGCAACGGGCTCAC CCTGAACTTCCTGGACTTGGAAGACATCAATGACTTTGGAGAGGATGATTCCCTGTACATCACCAAGGTG ACCACCATCCACATGGGCAATTACACCTGCCATGCTTCCGGCCACGAGCAGCTGTTCCAGACCCACGTCC

TGCAGGTGAATGTGCCGCCAGTCATCCGTGTCTATCCAGAGAGCCAGGCACAGGAGCCTGGAGTGGCAGC CAGCCTAAGATGCCATGCTGAGGGCATTCCCATGCCCAGAATCACTTGGCTGAAAAACGGCGTGGATGTC TCAACTCAGATGTCCAAACAGCTCTCCCTTTTAGCCAATGGGAGCGAACTCCACATCAGCAGTGTTCGGT ATGAAGACACAGGGGCATACACCTGCATTGCCAAAAATGAAGTGGGTGTGGATGAAGATATCTCCTCGCT CTTCATTGAAGACTCAGCTAGAAAGACCCTTGCAAACATCCTGTGGCGAGAGGAAGGCCTCAGCGTGGGA

AACATGTTCTATGTCTTCTCCGACGACGGTATCATCGTCATCCATCCTGTGGACTGTGAGATCCAGAGGC ACCTCAAACCCACGGAAAAGATTTTCATGAGCTATGAAGAAATCTGTCCTCAAAGAGAAAAAAATGCAAC CCAGCCCTGCCAGTGGGTATCTGCAGTCAATGTCCGGAACCGGTACATCTATGTGGCCCAGCCAGCACTG AGCAGAGTCCTTGTGGTCGACATCCAAGCCCAGAAAGTCCTACAGTCCATAGGTGTGGACCCTCTGCCGG CTAAGCTGTCCTATGACAAGTCACATGACCAAGTGTGGGTCCTGAGCTGGGGGGACGTGCACAAGTCCCG

ACCAAGTCTCCAGGTGATCACAGAAGCCAGCACCGGCCAGAGCCAGCACCTCATCCGCACACCCTTTGCA GGAGTGGATGATTTCTTCATTCCCCCAACAAACCTCATCATCAACCACATCAGGTTTGGCTTCATCTTCA ACAAGTCTGATCCTGCAGTCCACAAGGTGGACCTGGAAACAATGATGCCCCTCAAGACCATCGGCCTGCA CCACCATGGCTGCGTGCCCCAGGCCATGGCACACACCCACCTGGGCGGCTACTTCTTCATCCAGTGCCGA CAGGACAGCCCCGCCTCTGCTGCCCGACAGCTGCTCGTTGACAGTGTCACAGACTCTGTGCTTGGCCCCA

ATGGTGATGTAACAGGCACCCCACACACATCCCCCGACGGGCGCTTCATAGTCAGTGCTGCAGCTGACAG CCCCTGGCTGCACGTGCAGGAGATCACAGTGCGGGGCGAGATCCAGACCCTGTATGACCTGCAAATAAAC TCGGGCATCTCAGACTTGGCCTTCCAGCGCTCCTTCACTGAAAGCAATCAATACAACATCTACGCGGCTC TGCACATGGAGCCGGACCTGCTGTTCCTGGAGCTGTCCACGGGGAAGGTGGGCATGCTGAAGAACTTAAA GGAGCCACCCGCAGGGCCAGCTCAGCCCTGGGGGGGTACCCACAGAATCATGAGGGACAGTGGGCTGTTT

GGACAGTACCTCCTCACACCAGCCCGAGAGTCACTGTTCCTCATCAATGGGAGACAAAACACGCTGCGGT GTGAGGTGTCAGGTATAAAGGGGGGGACCACAGTGGTGTGGGTGGGTGAGGTACTCGAG

Table ABV. DNA sequence of assembly 268825997 (SEQ ID NO:234)

CTCGAGTACCTCACCCACCCACACCACTGTGGTCCCCCCCTTTATACCTGACACCTCACACCGCAGCGTG TTTTGTCTCCCATTGATGAGGAACAGTGACTCTCGGGCTGGTGTGAGGAGGTACTGTCCAAACAGCCCAC TGTCCCTCATGATTCTGTGGGTACCCCCCCAGGGCTGAGCTGGCCCTGCGGGTGGCTCCTTTAAGTTCTT CAGCATGCCCACCTTCCCCGTGGACAGCTCCAGGAACAGCAGGTCCGGCTCCGTGTGCAGAGCCGCGTAG ATGTTGTATTGATTGCTTTCAGTGAAGGAGCGCTGGAAGGCCAAGTCTGAGATGCCCGAGTTTATTTGCA

GGTCATACAGGGTCTGGATCTCGCCCCGCACTGTGATCTCCTGCACGTGCAGCCAGGGGCTGTCAGCTGC AGCACTGACTATGAAGCGCCCGTCGGGGGATGTGTGTGGGGTGCCTGTTACATCACCATTGGGGCCAAGC ACAGAGTCTGTGACACTGTCAACGAGCAGCTGTCGGGCAGCAGAGGCGGGGCTGTCCTGTCGGCACTGGA TGAAGAAGTAGCCGCCCAGGTGGGTGTGTGCCATGGCCTGGGGCACGCAGCCATGGTGGTGCAGGCCGAT GGTCTTGAGGGGCATCATTGTTTCCAGGTCCACCTTGTGGACTGTAGGATCAGACTTGTTGAAGATGAAG

CCAAACCTGATGTGGTTGATGATGAGGTTTGTTGGGGGAATGAAGAAATCATCCACTCCTGCAAAGGGTG TGCGGATGAGGTGCTGGCTCTGGCCGGTGCTGGCTTCTGTGATCACCTGGAGACTTGGTCGGGACTTGTG CACGTCCCCCCAGCTCAGGACCCACACTTGGTCATGTGACTTGTCATAGGACAGCTTAGCCGGCAGAGGG TCCACACCTATGGACTGTAGGACTTTCTGGGCTTGGATGTCGACCACAAGGACTCTGCTCAGTGCTGGCT GGGCCACATAGATGTACCGGTTCCGGACATTGACTGCAGATACCCACTGGCAGGGCTGGGTTGCATTTTT

TTCTCTTTGAGGACAGATTTCTTCATAGCTCATGAAAATCTTTTCCGTGGGTTTGAGGTGCCTCTGGATC TCACAGTCCACAGGATGGATGACGATGATACCGTCGTCGGAGAAGACATAGAACATGTTTCCCACGCTGA GGCCTTCCTCTCGCCACAGGATGTTTGCAAGGGTCTTTCTAGCTGAGTCTTCAATGAAGAGCGAGGAGAT ATCTTCATCCACACCCACTTCATTTTTGGCAATGCAGGTGTATGCCCCTGTGTCTTCATACCGAACACTG CTGATGTGGAGTTCGCTCCCATTGGCTAAAAGGGAGAGCTGTTTGGACATCTGAGTTGAGACATCCACGC

CGTTTTTCAGCCAAGTGATTCTGGGCATGGGAATGCCCTCAGCATGGCATCTTAGGCTGGCTGCCACTCC AGGCTCCTGTGCCTGGCTCTCTGGATAGACACGGATGACTGGCGGCACATTCACCTGCAGGACGTGGGTC TGGAACAGCTGCTCGTGGCCGGAAGCATGGCAGGTGTAATTGCCCATGTGGATGGTGGTCACCTTGGTGA TGTACAGGGAATCATCCTCTCCAAAGTCATTGATGTCTTCCAAGTCCAGGAAGTTCAGGGTGAGCCCGTT GCGCTTCCAGATGATTGGTGGCCTCAGGTCTCCATGGACGGCGCAGGTCAGCACTGTGCTCAGCCCCACG GTCACTGTGGTCACACTGACCCTGTCCTCGGGGGCGAGGCTGAGCTGAACCACTTGGAAGGCCATGTAGA

ACTCGCGGAGGGTCAGGGAGCTGTCACTGTTGTAATCGTCAAATCGGAGGAGGTCACCTGGTGAGCAACC AAGTAAGTCTTCATCCAGGTCCTGCTTCTTCAGCACATGCTGAGCCAGTTCGGAGCTGCTGAGGTGGCCA TTGCCATCTGCATCTAAGTCCCTGAACAGAGATTCCACCAGGAGGCGCTTCTGGGAGGCAGGGTCTTGTC TGCTGTCTCCTTCTTGGAGTGGCTGCAGACGGGTCTGGAGTGCCAGAAGGACATTCTTCAAGCGGGCGTA GCCGGCCATGGTGCACGTGTCACCTTTGAGGAAACAGTCCTTGCTGTGGATGACGGTGATCCTCTTTCCC

AGGAGGCAAGCAGCACGGTGGAGCTTACAGTGGTTTTCATAAAACCTCCCATCAGAGCCGCACACAGGCA CGTAGCTGGGCCTGCATGCCTCCAGGCACTGGCATTCGGGCTCCCCTGTCTTCCTGCTGAGCACGCACCG GCTCCCTCGGCTGCAGAACTTCTTCCCGCAGGAGGCCAGCAGCTCGTTGTGGCTGGAAAGCCCTTCTCTT CTTGTGACTTCAAAGCTTCTGGGCTCCTCTGCCTGTGACTCCCCCACACCCACATCCGGGCCTCTGCTGG TTCCTGGGTCCATCCACTCGAG

TABLE ABW TRANSLATED PROTEIN OF 268824728 (SEQ ID NO:235)

Frame: 1 - Nucleotide 1 to 2511

CTCGAGATGAAACCAGGAGGCTTTTGGCTGCATCTCACACTGCTCGGAGCCTCCCTGCCGGCTGCGCTGGGATGGATGGA L E M K P G G F W L H L T L L G A S L P A A L G W M D

CCCAGGAACCAGCAGAGGCCCGGATGTGGGTGTGGGGGAGTCACAGGCAGAGGAGCCCAGAAGCTTTGAAGTCACAAGAA P G T S R G P D V G V G E S Q A E E P R S F E V T R R

161 GAGAAGGGCTTTCCAGCCACAACGAGCTGCTGGCCTCCTGCGGGAAGAAGTTCTGCAGCCGAGGGAGCCGGTGCGTGCTC E G L S S H N E L L A S C G K K F C S R G S R C V L

241 AGCAGGAAGACAGGGGAGCCCGAATGCCAGTGCCTGGAGGCATGCAGGCCCAGCTACGTGCCTGTGTGCGGCTCTGATGG S R K T G E P E C Q C L E A C R P S Y V P V C G S D G

321 GAGGTTTTATGAAAACCACTGTAAGCTCCACCGTGCTGCTTGCCTCCTGGGAAAGAGGATCACCGTCATCCACAGCAAGG R F Y E N H C K L H R A A C L L G K R I T V I H S K D

401 ACTGTTTCCTCAAAGGTGACACGTGCACCATTGCCGGCTACGCCCGCTTGAAGAATGTCCTTCTGGCACTCCAGACCCGT C F L K G D T C T I A G Y A R L K N V L L A L Q T R

481 CTGCAGCCACTCCAAGAAGGAGACAGCAGACAAGACCCTGCCTCCCAGAAGCGCCTCCTGGTGGAATCTCTGTTCAGGGA L Q P L Q E G D S R Q D P A S Q K R L L V E S L F R D

CTTAGATGCAGATGGCAATGGCCACCTCAGCAGCTCCGAACTGGCTCAGCATGTGCTGAAGAAGCAGGACCTGGATGAAG L D A D G N G H L S S S E L A Q H V L K K Q D L D E D

ACTTACTTGGTTGCTCACCAGGTGACCTCCTCCGATTTGACGATTACAACAGTGACAGCTCCCTGACCCTCCGCGAGTTC L L G C S P G D L. L R F D D Y N S D S S L T L R E F

TACATGGCCTTCCAAGTGGTTCAGCTCAGCCTCGCCCCCGAGGACAGGGTCAGTGTGACCACAGTGACCGTGGGGCTGAG Y M A F Q V V Q L S L A P E D R V S V T T V T V G L S

CACAGTGCTGACCTGCGCCGTCCATGGAGACCTGAGGCCACCAATCATCTGGAAGCGCAACGGGCTCACCCTGAACTTCC

801 T V L T C A V H G D L R P P I I K R N G L T L N F L

881 TGGACTTGGAAGACATCAATGACTTTGGAGAGGATGATTCCCTGTACATCACCAAGGTGACCACCATCCACATGGGCAAT D L E D I N D F G E D D S L Y I T K V T T I H M G N

961 TACACCTGCCATGCTTCCGGCCACGAGCAGCTGTTCCAGACCCACGTCCTGCAGGTGAATGTGCCGCCAGTCATCCGTGT Y T C H A S G H E Q L F Q T H V L Q V N V P P V I R V

1041 CTATCCAGAGAGCCAGGCACAGGAGCCTGGAGTGGCAGCCAGCCTAAGATGCCATGCTGAGGGCATTCCCATGCCCAGAA Y P E S Q A Q E P G V A A S L R C H A E G I P M P R I

1121 TCACTTGGCTGAAAAACGGCGTGGATGTCTCAACTCAGATGTCCAAACAGCTCTCCCTTTTAGCCAATGGGAGCGAACTC T W L K W G V D V S T Q M S K Q L S L L A N G S E L 1201 V R E D K N

1281 CTCCTCGCTCTTCATTGAAGACTCAGCTAGAAAGACCCGCCTCAGCGTGGGAAACATGTTCTATGTCTTCTCCGACGACG S S L F I E D S A R K T R L S V G N M F Y V F S D D G

1361 GTATCATCGTCATCCATCCTGTGGACTGTGAGATCCAGAGGCACCTCAAACCCACGGAAAAGATTTTCATGAGCTATGAA I I V I H P V D C E I Q R H L K P T E K I F S Y E

1441 GAAATCTGTCCTCAAAGAGAAAAAAATGCAACCCAGCCCTGCCAGTGGGTATCTGCAGTCAATGTCCGGAACCGGTACAT E l C P Q R E K N A T Q P C Q W V S A V N V R N R Y I

1521 CTATGTGGCCCAGCCAGCACTGAGCAGAGTCCTTGTGGTCGACATCCAAGCCCAGAAAGTCCTACAGTCCATAGGTGTGG Y V A Q P A L S R V L V V D I Q A Q K V L Q S I G V D

1601 ACCCTCTGCCGGCTAAGCTGTCCTATGACAAGTCACATGACCAAGTGTGGGTCCTGAGCTGGGGGGACGTGCACAAGTCC P L P A K L S Y D K S H D Q V W V L S W G D V H K S

CGACCAAGTCTCCAGGTGATCACAGAAGCCAGCACCGGCCAGAGCCAGCACCTCATCCGCACACCCTTTGCAGGAGTGGA R P S L Q V 1 T E A S T G Q S Q H L I R T P F A G V D

1761 TGATTTCTTCATTCCCCCAACAAACCTCATCATCAACCACATCAGGTTTGGCTTCATCTTCAACAAGTCTGATCCTGCAG D F F I P P T N L I I N H I R F G F I F K S D P A V

1841 TCCACAAGGTGGACCTGGAAACAATGATGCCCCTCAAGACCATCGGCCTGCACCACCATGGCTGCGTGCCCCAGGCCATG H K V D L E T M M P L K T I G L H H H G C V P Q A M

1921 GCACACACCCACCTGGGCGGCTACTTCTTCATCCAGTGCCGACAGGACAGCCCCGCCTCTGCTGCCCGACAGCTGCTCGT A H T H L G G Y F F I Q C R Q D S P A S A A R Q L L V

2001 TGACAGTGTCACAGACTCTGTGCTTGGCCCCAATGGTGATGTAACAGGCACCCCACACACATCCCCCGACGGGCGCTTCA D S V T D S V L G P N G D V T G T P H T S P D G R F I

2081 TAGTCAGTGCTGCAGCTGACAGCCCCTGGCTGCACGTGCAGGAGATCACAGTGCGGGGCGAGATCCAGACCCTGTATGAC V S A A A D S P W L H V Q E I T V R G E I Q T L Y D

2161 CTGCAAATAAACTCGGGCATCTCAGACTTGGCCTTCCAGCGCTCCTTCACTGAAAGCAATCAATACAACATCTACGCGGC L Q I N S G I S D L A F Q R S F T E S N Q Y N I Y A A

TCTGCACATGGAGCCGGACCTGCTGTTCCTGGAGCTGTCCACGGGGAAGGTGGGCATGCTGAAGAACTTAAAGGAGCCAC L H M E P D L L F L E L S T G K V G M L K N B K E P P

2321 CCGCAGGGCCAGCTCAGCCCTGGGGGGGTACCCACAGAATCATGAGGGACAGTGGGCTGTTTGGACAGTACCTCCTCACA A G P A Q P W G G T H R I M R D S G F G Q Y L T

CCAGCCCGAGAGTCACTGTTCCTCATCAATGGGAGACAAAACACGCTGCGGTGTGAGGTGTCAGGTATAAAGGGGGGGAC P A R E S L F L I N G R Q N T L R C E V S G I K G G T

2481 CACAGTGGTGTGGGTGGGTGAGGTACTCGAG T V V V G E V L E

TABLE ABX. TRANSLATED PROTEIN OF 268825987 (SEQ ID NO:236)

Frame: 1 - Nucleotide 1 to 2439

CTCGAGATGAAACCAGGAGGCTTTTGGCTGCATCTCACACTGCTCGGAGCCTCCCTGCCGGCTGCGCTGGGATGGATGGA L E M K P G G F L H L T L L G A S L P A A L G M D

81 CCCAGGAACCAGCAGAGGCCCGGATGTGGGTGTGGGGGAGTCACAGGCAGAGGAGCCCAGAAGCTTTGAAGTCACAAGAA P G T S R G P D V G V G E S Q A E E P R S F E V T R R lεi GAGAAGGGCTTTCCAGCCACAACGAGCTGCTGGCCTCCTGCGGGAAGAAGTTCTGCAGCCGAGGGAGCCGGTGCGTGCTC E G L S S H N E L L A S C G K K F C S R G S R C V L

241 AGCAGGAAGACAGGGGAGCCCGAATGCCTGGGAAAGAGGATCACCGTCATCCACAGCAAGGACTGTTTCCTCAAAGGTGA S R K T G E P E C L G K R I T V I H S K D C F L K G D

321 CACGTGCACCATGGCCGGCTACGCCCGCTTGAAGAATGTCCTTCTGGCACTCCAGACCCGTCTGCAGCCACTCCAAGAAG T C T M A G Y A R L K N V L L A L Q T R L Q P L Q E G

401 GAGACAGCAGACAAGACCCTGCCTCCCAGAAGCGCCTCCTGGTGGAATCTCTGTTCAGGGACTTAGATGCAGATGGCAAT D S R Q D P A S Q K R L L V E S L F R D L D A D G N

481 GGCCACCTCAGCAGCTCCGAACTGGCTCAGCATGTGCTGAAGAAGCAGGACCTGGATGAAGACTTACTTGGTTGCTCACC G H L S S S E L A Q H V L K K Q D L D E D L L G C S P

561 AGGTGACCTCCTCCGATTTGACGATTACAACAGTGACAGCTCCCTGACCCTCCGCGAGTTCTACATGGCCTTCCAAGTGG G D L L R F D D Y N S D S S L T L R E F Y M A F Q V V TTCAGCTCAGCCTCGCCCCCGAGGACAGGGTCAGTGTGACCACAGTGACCGTGGGGCTGAGCACAGTGCTGACCTGCGCC Q L S L A P E D R V S V T T V T V G L S T V L T C A

GTCCATGGAGACCTGAGGCCACCAATCATCTGGAAGCGCAACGGGCTCACCCTGAACTTCCTGGACTTGGAAGACATCAA V H G D L R P P I I W K R N G L T L N F L D L E D I N

801 TGACTTTGGAGAGGATGATTCCCTGTACATCACCAAGGTGACCACCATCCACATGGGCAATTACACCTGCCATGCTTCCG D F G E D D S L Y I T K V T T I H M G N Y T C H A S G

GCCACGAGCAGCTGTTCCAGACCCACGTCCTGCAGGTGAATGTGCCGCCAGTCATCCGTGTCTATCCAGAGAGCCAGGCA H E Q L F Q T H V L Q V N V P P V I R V Y P E S Q A

961 CAGGAGCCTGGAGTGGCAGCCAGCCTAAGATGCCATGCTGAGGGCATTCCCATGCCCAGAATCACTTGGCTGAAAAACGG Q E P G V A A S L R C H A E G I P M P R I T W L K N G

CGTGGATGTCTCAACTCAGATGTCCAAACAGCTCTCCCTTTTAGCCAATGGGAGCGAACTCCACATCAGCAGTGTTCGGT V D V S T Q M S K Q L S L L A N G S E L H I S S V R Y

1121 ATGAAGACACAGGGGCATACACCTGCATTGCCAAAAATGAAGTGGGTGTGGATGAAGATATCTCCTCGCTCTTCATTGAA E D T G A Y T C I A K N E V G V D E D I S S L F I E

1201 GACTCAGCTAGAAAGACCCTTGCAAACATCCTGTGGCGAGAGGAAGGCCTCAGCGTGGGAAACATGTTCTATGTCTTCTC D S A R R T L A N I L W R E E G L S V G N M F Y V F S

1281 CGACGACGGTATCATCGTCATCCATCCTGTGGACTGTGAGATCCAGAGGCACCTCAAACCCACGGAAAAGATTTTCATGA D D G I I V I H P V D C E I Q R H L K P T E K I F S

GCTATGAAGAAATCTGTCCTCAAAGAGAAAAAAATGCAACCCAGCCCTGCCAGTGGGTATCTGCAGTCAATGTCCGGAAC Y E E I C P Q R E K N A T Q P C Q W V S A V N V R N

1441 CGGTACATCTATGTGGCCCAGCCAGCACTGAGCAGAGTCCTTGTGGTCGACATCCAAGCCCAGAAAGTCCTACAGTCCAT R Y I Y V A Q P A L S R V L V V D I Q A Q R V L Q S I

1521 AGGTGTGGACCCTCTGCCGGCTAAGCTGTCCTATGACAAGTCACATGACCAAGTGTGGGTCCTGAGCTGGGGGGACGTGC G V D P L P A K L S Y D K S H D Q V V L S G D V H

ACAAGTCCCGACCAAGTCTCCAGGTGATCACAGAAGCCAGCACCGGCCAGAGCCAGCACCTCATCCGCACACCCTTTGCA K S R P S L Q V I T E A S T G Q S Q H L I R T P F A

GGAGTGGATGATTTCTTCATTCCCCCAACAAACCTCATCATCAACCACATCAGGTTTGGCTTCATCTTCAACAAGTCTGA G V D D F F I P P T N L I I N H I R F G F I F N K S D _gl TCCTGCAGTCCACAAGGTGGACCTGGAAACAATGATGCCCCTCAAGACCATCGGCCTGCACCACCATGGCTGCGTGCCCC P A V H K V D L E T M M P L K T I G L H H H G C V P Q

₁ AGGCCATGGCACACACCCACCTGGGCGGCTACTTCTTCATCCAGTGCCGACAGGACAGCCCCGCCTCTGCTGCCCGACAG A M A H T H L G G Y F F I Q C R Q D S P A S A A R Q

19₂1 ^CT5CTCGTTGACAGTGTCACAGACTCTGTGCTTGGCCCCAATGGTGATGTAACAGGCACCCCACACACATCCCCCGACGG L L V D S V T D S V L G P N G D V T G T P H T S P D G

GCGCTTCATAGTCAGTGCTGCAGCTGACAGCCCCTGGCTGCACGTGCAGGAGATCACAGTGCGGGGCGAGATCCAGACCC R F I V S A A A D S P W L H V Q E I T V R G E I Q T L

2081 TGTATGACCTGCAAATAAACTCGGGCATCTCAGACTTGGCCTTCCAGCGCTCCTTCACTGAAAGCAATCAATACAACATC Y D L Q I N S G I S D L A F Q R S F T E S N Q Y N I 2161 TACGCGGCTCTGCACATGGAGCCGGACCTGCTGTTCCTGGAGCTGTCCACGGGGAAGGTGGGCATGCTGAAGAACTTAAA Y A A L H M E P D L L F L E L S T G K V G M L K N L K 2241 GGAGCCACCCGCAGGGCCAGCTCAGCCCTGGGGGGGTACCCACAGAATCATGAGGGACAGTGGGCTGTTTGGACAGTACC E P P A G P A Q P W G G T H R I M R D S G L F G Q Y L 2321 TCCTCACACCAGCCCGAGAGTCACTGTTCCTCATCAATGGGAGACAAAACACGCTGCGGTGTGAGGTGTCAGGTATAAAG I, T P A R E S TJ F L I N R R O N T, R C E V R G T ' 2401 GGGGGGACCACAGTGGTGTGGGTGGGTGAGGTACTCGAG G G T T V V W V G E V L E

TABLE AB Y. TRANSLA TED PROTEIN OF 268825997 (SEQ ID NO:237)

Frame: -1 - Nucleotide 1 to 2472

₁ CTCGAGTGGATGGACCCAGGAACCAGCAGAGGCCCGGATGTGGGTGTGGGGGAGTCACAGGCAGAGGAGCCCAGAAGCTT L E W M D P G T S R G P D V G V G E S Q A E E P R S F

₈₁ TGAAGTCACAAGAAGAGAAGGGCTTTCCAGCCACAACGAGCTGCTGGCCTCCTGCGGGAAGAAGTTCTGCAGCCGAGGGA E V T R R E G L S S H N E L L A S C G K K F C S R G S

161 E A C R

TGCGGCTCTGATGGGAGGTTTTATGAAAACCACTGTAAGCTCCACCGTGCTGCTTGCCTCCTGGGAAAGAGGATCACCGT C G S D G R F Y E N H C K L H R A A C L L G R I T V

CATCCACAGCAAGGACTGTTTCCTCAAAGGTGACACGTGCACCATGGCCGGCTACGCCCGCTTGAAGAATGTCCTTCTGG I H S K D C F L K G D T C T M A G Y A R L K N V L L A

CACTCCAGACCCGTCTGCAGCCACTCCAAGAAGGAGACAGCAGACAAGACCCTGCCTCCCAGAAGCGCCTCCTGGTGGAA L Q T R L Q P L Q E G D S R Q D P A S Q K R L L. V E

... TCTCTGTTCAGGGACTTAGATGCAGATGGCAATGGCCACCTCAGCAGCTCCGAACTGGCTCAGCATGTGCTGAAGAAGCA S L F R D L D A D G N G H L S S S E B A Q H V L K K Q

_5S1 GGACCTGGATGAAGACTTACTTGGTTGCTCACCAGGTGACCTCCTCCGATTTGACGATTACAACAGTGACAGCTCCCTGA D L D E D L L G C S P G D L L R F D D Y N S D S S L T

_S41 CCCTCCGCGAGTTCTACATGGCCTTCCAAGTGGTTCAGCTCAGCCTCGCCCCCGAGGACAGGGTCAGTGTGACCACAGTG L R E F Y M A F Q V V Q L S L A P E D R V S V T T V

ACCGTGGGGCTGAGCACAGTGCTGACCTGCGCCGTCCATGGAGACCTGAGGCCACCAATCATCTGGAAGCGCAACGGGCT T V G L S T V L T C A V H G D L R P P I I K R N G L

CACCCTGAACTTCCTGGACTTGGAAGACATCAATGACTTTGGAGAGGATGATTCCCTGTACATCACCAAGGTGACCACCA T L N F L D L E D I N D F G E D D S L Y I T K V T T I

TCCACATGGGCAATTACACCTGCCATGCTTCCGGCCACGAGCAGCTGTTCCAGACCCACGTCCTGCAGGTGAATGTGCCG H M G N Y T C H A S G H E Q L F Q T H V L Q V N V P

CCAGTCATCCGTGTCTATCCAGAGAGCCAGGCACAGGAGCCTGGAGTGGCAGCCAGCCTAAGATGCCATGCTGAGGGCAT P V I R V Y P E S Q A Q E P G V A A S L R C H A E G I

1041 TCCCATGCCCAGAATCACTTGGCTGAAAAACGGCGTGGATGTCTCAACTCAGATGTCCAAACAGCTCTCCCTTTTAGCCA P M P R I T L K N G V D V S T Q M S K Q L S L L A N

1121 ATGGGAGCGAACTCCACATCAGCAGTGTTCGGTATGAAGACACAGGGGCATACACCTGCATTGCCAAAAATGAAGTGGGT G S E L H I S S V R Y E D T G A Y T C I A K N E V G

1201 GTGGATGAAGATATCTCCTCGCTCTTCATTGAAGACTCAGCTAGAAAGACCCTTGCAAACATCCTGTGGCGAGAGGAAGG V D E D I S S L F I E D S A R K T L A N I L R E E G

1281 CCTCAGCGTGGGAAACATGTTCTATGTCTTCTCCGACGACGGTATCATCGTCATCCATCCTGTGGACTGTGAGATCCAGA L S V G N M F Y V F S D D G I I V I H P V D C E I Q R

1361 GGCACCTCAAACCCACGGAAAAGATTTTCATGAGCTATGAAGAAATCTGTCCTCAAAGAGAAAAAAATGCAACCCAGCCC H L K P T E K I F M S Y E E I C P Q R E K N A T Q P

1441 ^TG CAGTGGGTATCTGCAGTCAATGTCCGGAACCGGTACATCTATGTGGCCCAGCCAGCACTGAGCAGAGTCCTTGTGGT C Q V S A V N V R N R Y I Y V A Q P A L S R V L V V

CGACATCCAAGCCCAGAAAGTCCTACAGTCCATAGGTGTGGACCCTCTGCCGGCTAAGCTGTCCTATGACAAGTCACATG D I Q A Q K V L Q S I G V D P L P A K L S Y D K S H D

ACCAAGTGTGGGTCCTGAGCTGGGGGGACGTGCACAAGTCCCGACCAAGTCTCCAGGTGATCACAGAAGCCAGCACCGGC Q V V L S W G D V H K S R P S L Q V I T E A S T G

1681 CAGAGCCAGCACCTCATCCGCACACCCTTTGCAGGAGTGGATGATTTCTTCATTCCCCCAACAAACCTCATCATCAACCA Q S Q H L I R T P F A G V D D F F I P P T N L I I N H _g- CATCAGGTTTGGCTTCATCTTCAACAAGTCTGATCCTACAGTCCACAAGGTGGACCTGGAAACAATGATGCCCCTCAAGA I R F G F I F N K S D P T V H K V D L E T M M P L K T

₈₄- CCATCGGCCTGCACCACCATGGCTGCGTGCCCCAGGCCATGGCACACACCCACCTGGGCGGCTACTTCTTCATCCAGTGC I G L H H H G C V P Q A M A H T H L G G Y F F I Q C

CGACAGGACAGCCCCGCCTCTGCTGCCCGACAGCTGCTCGTTGACAGTGTCACAGACTCTGTGCTTGGCCCCAATGGTGA R Q D S P A S A A R Q L L V D S V T D S V L G P N G D

₁ TGTAACAGGCACCCCACACACATCCCCCGACGGGCGCTTCATAGTCAGTGCTGCAGCTGACAGCCCCTGGCTGCACGTGC V T G T P H T S P D G R F I V S A A A D S P W L H V Q

2081 ^AGGAGATCACAGTGCGGGGCGAGATCCAGACCCTGTATGACCTGCAAATAAACTCGGGCATCTCAGACTTGGCCTTCCAG E I T V R G E I Q T L Y D L Q I N S G I S D L A F Q

2161 CGCTCCTTCACTGAAAGCAATCAATACAACATCTACGCGGCTCTGCACACGGAGCCGGACCTGCTGTTCCTGGAGCTGTC R S F T E S N Q Y N I Y A A L H T E P D L L F L E lL S

2241 CACGGGGAAGGTGGGCATGCTGAAGAACTTAAAGGAGCCACCCGCAGGGCCAGCTCAGCCCTGGGGGGGTACCCACAGAA T G K V G M L K N L K E P P A G P A Q P G G T H R I

2321 ^TCATGAGGGACAGTGGGCTGTTTGGACAGTACCTCCTCACACCAGCCCGAGAGTCACTGTTCCTCATCAATGGGAGACAA M R D S G L F G Q Y L L T P A R E S L F L I N G R Q

2401 AACACGCTGCGGTGTGAGGTGTCAGGTATAAAGGGGGGGACCACAGTGGTGTGGGTGGGTGAGGTACTCGAG N T L R C E V S G I K G G T T V V V G E V L E TABLE ABZ. SEQUENCES OF 275698334

Translated Protein - Frame: -1 - Nucleotide 1 to 2538 Polynucleotide (SEQ ID NO:238)

Polypeptide (SEQ ID NO:239)

CTCGAGATGAAACCAGGAGGCTTTTGGCTGCATCTCACACTGCTCGGAGCCTCCCTGCCGGCTGCGCTGGGATGGATGGA L E M K P G G P W L H L T L L G A S L P A A L G W M D

CCCAGGAACCAGCAGAGGCCCGGATGTGGGTGTGGGGGAGTCACAGGCAGAGGAGCCCAGAAGCTTTGAAGTCACAAGAA P G T S R G P D V G V G E S Q A E E P R S F E V T R R

GAGAAGGGCTTTCCAGCCACAACGAGCTGCTGGCCTCCTGCGGGAAGAAGTTCTGCAGCCGAGGGAGCCGGTGCGTGCTC E G L S S H N E L L A S C G K K F C S R G S R C V L

241 AGCAGGAAGACAGGGGAGCCCGAATGCCAGTGCCTGGAGGCATGCAGGCCCAGCTACGTGCCTGTGTGCGGCTCTGATGG S R K T G E P E C Q C L E A C R P S Y V P V C G S D G

GAGGTTTTATGAAAACCACTGTAAGCTCCACCGTGCTGCTTGCCTCCTGGGAAAGAGGATCACCGTCATCCACAGCAAGG

321 R F Y E N H C K L H R A A C L L G K R I T V I H S K D

401 ACTGTTTCCTCAAAGGTGACACGTGCACCATGGCCGGCTACGCCCGCTTGAAGAATGTCCTTCTGGCACTCCAGACCCGT C F L K G D T C T M A G Y A R L K N V L L A L Q T R 481 CTGCAGCCACTCCAAGAAGGAGACAGCAGACAAGACCCTGCCTCCCAGAAGCGCCTCCTGGTGGAATCTCTGTTCAGGGA L Q P L Q E G D S R Q D P A S Q K R L L V E S L F R D

CTTAGATGCAGATGGCAATGGCCACCTCAGCAGCTCCGAACTGGCTCAGCATGTGCTGAAGAAGCAGGACCTGGATGAAG

561 L D A D G N G H L S S S E L A Q H V L K K Q D L D E D

ACTTACTTGGTTGCTCACCAGGTGACCTCCTCCGATTTGACGATTACAACAGTGACAGCTCCCTGACCCTCCGCGAGTTC

641 L L G C S P G D L L R F D D Y N S D S S L T L R E F

721 TACATGGCCTTCCAAGTGGTTCAGCTCAGCCTCGCCCCCGAGGACAGGGTCAGTGTGACCACAGTGACCGTGGGGCTGAG Y M A F Q V V Q L S L A P E -D R V S V T T V T V G L S

801 CACAGTGCTGACCTGCGCCGTCCATGGAGACCTGAGGCCACCAATCATCTGGAAGCGCAACGGGCTCACCCTGAACTTCC T V L T C A V H G D L R P P 1 I W K R N G L T L N F L

881 TGGACTTGGAAGACATCAATGACTTTGGAGAGGATGATTCCCTGTACATCACCAAGGTGACCACCATCCACATGGGCAAT D L E D I N D F G E D D S L Y I T V T T I H M G N

TACACCTGCCATGCTTCCGGCCACGAGCAGCTGTTCCAGACCCACGTCCTGCAGGTGAATGTGCCGCCAGTCATCCGTGT

961 Y T C H A S G H E Q L F Q T H V L Q V N V P P V T R V

CTATCCAGAGAGCCAGGCACAGGAGCCTGGAGTGGCAGCCAGCCTAAGATGCCATGCTGAGGGCATTCCCATGCCCAGAA

1041 Y P E S Q A Q E P G V A A S L R C H A E G I P M P R I

1121 TCACTTGGCTGAAAAACGGCGTGGATGTCTCAACTCAGATGTCCAAACAGCTCTCCCTTTTAGCCAATGGGAGCGAACTC T L K N G V D V S T Q M S K Q L S L L A N G S E L

CACATCAGCAGTGTTCGGTATGAAGACACAGGGGCATACACCTGCATTGCCAAAAATGAAGTGGGTGTGGATGAAGATAT

1201 H I S S V R Y E D T G A Y T C I A K N E V G V D E D I

CTCCTCGCTCTTCATTGAAGACTCAGCTAGAAAGACCCTTGCAAACATCCTGTGGCGAGAGGAAGGCCTCAGCGTGGGAA

1281 S S L F I E D S A R K T L A N I L R E E G L S V G N

ACATGTTCTATGTCTTCTCCGACGACGGTATCATCGTCATCCATCCTGTGGACTGTGAGATCCAGAGGCACCTCAAACCC

1361 M F Y V F S D D G I I V I H P V D C E I Q R H L K P

ACGGAAAAGATTTTCATGAGCTATGAAGAAATCTGTCCTCAAAGAGAAAAAAATGCAACCCAGCCCTGCCAGTGGGTATC

1441 T E K I F M S Y E E I C P Q R E K N A T Q P C Q W V S

TGCAGTCAATGTCCGGAACCGGTACATCTATGTGGCCCAGCCAGCACTGAGCAGAGTCCTTGTGGTCGACATCCAAGCCC

1521 A V N V R N R Y I Y V A Q P A L S R V L V V D I Q A Q

AGAAAGTCCTACAGTCCATAGGTGTGGACCCTCTGCCGGCTAAGCTGTCCTATGACAAGTCACATGACCAAGTGTGGGTC

1601 K V L Q S I G V D P L P A K L S Y D K S H D Q V V

CTGAGCTGGGGGGACGTGCACAAGTCCCGACCAAGTCTCCAGGTGATCACAGAAGCCAGCACCGGCCAGAGCCAGCACCT

1681 L S W G D V H K S R P S L Q V I T E A S T G Q S Q H L

CATCCGCACACCCTTTGCAGGAGTGGATGATTTCTTCATTCCCCCAACAAACCTCATCATCAACCACATCAGGTTTGGCT 1761 I R T P F A G V D D F F I P P T N L I I N H I R F G F

TCATCTTCAACAAGTCTGATCCTGCAGTCCACAAGGTGGACCTGGAAACAATGATGCCCCTCAAGACCATCGGCCTGCAC

1841 I F N K S D P A V H K V D L E T M M P L K T I G L H

CACCATGGCTGCGTGCCCCAGGCCATGGCACACACCCACCTGGGCGGCTACTTCTTCATCCAGTGCCGACAGGACAGCCC 1921 H H G C V P Q A M A H T H L G G Y F F I Q C R Q D S P 2001 CGCCTCTGCTGCCCGACAGCTGCTCGTTGACAGTGTCACAGACTCTGTGCTTGGCCCCAATGGTGATGTAACAGGCACCC A S A A R Q L L V D S V T D S V L G P N G D V T G T P

2081 CACACACATCCCCCGACGGGCGCTTCATAGTCAGTGCTGCAGCTGACAGCCCCTGGCTGCACGTGCAGGAGATCACAGTG H T S P D G R F I V S A A A D S P L H V Q E I T V

2161 CGGGGCGAGATCCAGACCCTGTATGACCTGCAAATAAACTCGGGCATCTCAGACTTGGCCTTCCAGCGCTCCTTCACTGA G E I Q T L Y D L Q I N S G I S D L A F Q R S F T E

2241 AAGCAATCAATACAACATCTACGCGGCTCTGCACATGGAGCCGGACCTGCTGTTCCTGGAGCTGTCCACGGGGAAGGTGG S N Q Y N I Y A A L H M E P D L L F L E L S T G K V G

2321 GCATGCTGAAGAACTTAAAGGAGCCACCCGCAGGGCCAGCTCAGCCCTGGGGGGGTACCCACAGAATCATGAGGGACAGT M L K N L K E P P A G P A Q P G G T H R I M R D S

2401 GGGCTGTTTGGACAGTACCTCCTCACACCAGCCCGAGAGTCACTGTTCCTCATCAATGGGAGACAAAACACGCTGCGGTG .G F G Q Y L L T P A R E S L F L I N G R Q N T L R C

2481 TGAGGTGTCAGGTATAAAGGGGGGGACCACAGTGGTGTGGGTGGGTGAGGTACTCGAG E V S G I K G G T T V V W V G E V L E

Other inserts encoding CG52643-02 were sequenced using vector-specific Ml 3 Forward and Ml 3 Reverse primers, and gene-specific primers as described above. For assemblies 268824728 and 268825987 the following gene-specific primers were used:

Table ABO

For

assembly 268825997 the following gene-specific primers were used: Table ABP

The insert assemblies 268824728 (SEQ ID NO: 268 and SEQ ID NO:269) and

268825987 (SEQ ID NO: XX and SEQ ID NO:XX) were found to encode an open reading frame between residues 1 and 842, and assembly 268825997 (SEQ ID NO: 270 and SEQ

ID NO:271) was found to encode an open reading frame between residues 23 and 842 of the target sequence of CG52643-02. The protein associated with 268825997 is encoded in a negative reading frame. The sequence shown has been reverse-complemented and renumbered to allow reading ofthe protein in the expected N to C direction. The cloned inserts differ from the original sequence. Assembly 268824728 has a deletion of 9 amino acids (439-447) and two amino acid changes: M433I and T757M. Assembly 268825987 has a 33 amino acid deletion (88-120) and one amino acid change: T757M. Assembly

268825997 one amino acid change: A620T. For assembly 275698334 the following gene-specific primers were used: Table ABQ

The insert assembly 275698334 was found to encode an open reading frame between residues 1 and 842 ofthe target sequence of CG52643-02. The cloned insert differs from the original sequence at one position: T757M. The protein associated with 275698334 is encoded in a negative reading frame. The sequence shown below has been reverse-complemented and renumbered to allow reading ofthe protein in the expected N to C direction. EQUIVALENTS

Although particular embodiments have been disclosed herein in detail, this has been done by way of example for purposes of illustration only, and is not intended to be limiting with respect to the scope ofthe appended claims, which follow. In particular, it is contemplated by the inventors that various substitutions, alterations, and modifications may be made to the invention without departing from the spirit and scope ofthe invention as defined by the claims. The choice of nucleic acid starting material, clone of interest, or library type is believed to be a matter of routine for a person of ordinary skill in the art with knowledge ofthe embodiments described herein. Other aspects, advantages, and modifications considered to be within the scope ofthe following claims.

Claims

WHAT IS CLAIMED IS:

1. An isolated polypeptide comprising an amino acid sequence selected from the group consisting of:

(a) a mature form of an amino acid sequence selected from the group consisting of SEQ ID NOS:2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 102, 104, 106, 108, 1 1 1, 1 14, 116, 1 18, 120, 123, 125, 136, 138, 140, 142, 144, 146, 148, 150, 152, 154, 156, 158, 160, 162, 164, and 167;

(b) a variant of a mature form of an amino acid sequence selected from the group consisting of SEQ ID NOS:2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 102, 104, 106, 108, 11 1, 1 14, 1 16, 118, 120, 123, 125, 136, 138, 140, 142, 144, 146, 148, 150, 152, 154, 156, 158, 160, 162, 164, and 167, wherein one or more amino acid residues in said variant differs from the amino acid sequence of said mature form, provided that said variant differs in no more than 15% ofthe amino acid residues from the amino acid sequence of said mature form;

(c) an amino acid sequence selected from the group consisting of SEQ ID NOS:2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 102, 104, 106, 108, 111, 1 14, 1 16, 1 18, 120, 123, 125, 136, 138, 140, 142, 144, 146, 148, 150, 152, 154, 156, 158, 160, 162, 164, and 167; and

(d) a variant of an amino acid sequence selected from the group consisting of SEQ ID NOS:2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 102, 104, 106, 108, 1 11 , 1 14, 1 16, 118, 120, 123, 125, 136, 138, 140, 142, 144, 146, 148, 150, 152, 154, 156, 158, 160, 162, 164, and 167, wherein one or more amino acid residues in said variant differs from the amino acid sequence of said mature form, provided that said variant differs in no more than 15% of amino acid residues from said amino acid sequence.

2 The polypeptide of claim 1, wherein said polypeptide comprises the amino acid sequence of a naturally-occurring allelic variant of an amino acid sequence selected from the group consisting of SEQ ID NOS :2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 102, 104, 106, 108, 111, 114, 1 16, 118, 120, 123, 125, 136, 138, 140, 142, 144, 146, 148, 150, 152, 154, 156, 158, 160, 162, 164, and 167.

3. The polypeptide of claim 2, wherein said allelic variant comprises an amino acid sequence that is the translation of a nucleic acid sequence differing by a single nucleotide from a nucleic acid sequence selected from the group consisting of SEQ ID NOS:l, 3, 5, 7, 9, 1 1, 13, 15, 17, 19, 21, 23, 101 , 103, 105, 107, 109, 112, 1 15, 117, 119, 121, 124, 135, 137, 139, 141, 143, 145, 147, 149, 151, 153, 155, 157, 159, 161, 163, 165, and 166.

4. The polypeptide of claim 1, wherein the amino acid sequence of said variant comprises a conservative amino acid substitution.

5. An isolated nucleic acid molecule comprising a nucleic acid sequence encoding a polypeptide comprising an amino acid sequence selected from the group consisting of:

(a) a mature form of an amino acid sequence selected from the group consisting of SEQ ID OS:2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 102, 104, 106, 108, 1 1 1, 1 14, 1 16, 1 18, 120, 123, 125, 136, 138, 140, 142, 144, 146, 148, 150, 152, 154, 156, 158, 160, 162, 164, and 167;

(b) a variant of a mature form of an amino acid sequence selected from the group consisting of SEQ ID NOS:2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 102, 104, 106, 108, 11 1, 1 14, 116, 1 18, 120, 123, 125, 136, 138, 140, 142, 144, 146, 148, 150, 152, 154, 156, 158, 160, 162, 164, and 167, wherein one or more amino acid residues in said variant differs from the amino acid sequence of said mature form, provided that said variant differs in no more than 15% ofthe amino acid residues from the amino acid sequence of said mature form;

(c) an amino acid sequence selected from the group consisting of SEQ ID NOS:2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 102, 104, 106, 108, 1 1 1, 1 14, 1 16, 118, 120, 123, 125, 136, 138, 140, 142, 144, 146, 148, 150, 152, 154, 156, 158, 160, 162, 164, and 167;

(d) a variant of an amino acid sequence selected from the group consisting SEQ ID NOS:2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 102, 104, 106, 108, 1 1 1, 114, 1 16, 1 18, 120, 123, 125, 136, 138, 140, 142, 144, 146, 148, 150, 152, 154, 156, 158, 160, 162, 164, and 167, wherein one or more amino acid residues in said variant differs from the amino acid sequence of said mature form, provided that said variant differs in no more than 15%> of amino acid residues from said amino acid sequence; (e) a nucleic acid fragment encoding at least a portion of a polypeptide comprising an amino acid sequence chosen from the group consisting of SEQ ID NOS:2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 102, 104, 106, 108, 1 1 1, 1 14, 116, 118, 120, 123, 125, 136, 138, 140, 142, 144, 146, 148, 150, 152, 154, 156, 158, 160, 162, 164, and 167, or a variant of said polypeptide, wherein one or more amino acid residues in said variant differs from the amino acid sequence of said mature form, provided that said variant differs in no more than 15% of amino acid residues from said amino acid sequence; and

(f) a nucleic acid molecule comprising the complement of (a), (b), (c), (d) or (e).

6. The nucleic acid molecule of claim 5, wherein the nucleic acid molecule comprises the nucleotide sequence of a naturally-occurring allelic nucleic acid variant.

7. The nucleic acid molecule of claim 5, wherein the nucleic acid molecule encodes a polypeptide comprising the amino acid sequence of a naturally-occurring polypeptide variant.

8. The nucleic acid molecule of claim 5, wherein the nucleic acid molecule differs by a single nucleotide from a nucleic acid sequence selected from the group consisting of SEQ ID NOS:l, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 101, 103, 105, 107, 109, 112, 115, 117, 119, 121, 124, 135, 137, 139, 141, 143, 145, 147, 149, 151, 153, 155, 157, 159, 161, 163, 165, and 166.

9. The nucleic acid molecule of claim 5, wherein said nucleic acid molecule comprises a nucleotide sequence selected from the group consisting of:

(a) a nucleotide sequence selected from the group consisting of SEQ ID NOS:l, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 101, 103, 105, 107, 109, 1 12, 1 15, 117, 119, 121, 124, 135, 137, 139, 141, 143, 145, 147, 149, 151, 153, 155, 157, 159, 161, 163, 165, and 166;

(b) a nucleotide sequence differing by one or more nucleotides from a nucleotide sequence selected from the group consisting of SEQ ID NOS:l, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 101, 103, 105, 107, 109, 112, 1 15, 117, 1 19, 121, 124, 135, 137, 139, 141, 143, 145, 147, 149, 151, 153, 155, 157, 159, 161, 163, 165, and 166, provided that no more than 20% ofthe nucleotides differ from said nucleotide sequence;

(c) a nucleic acid fragment of (a); and

(d) a nucleic acid fragment of (b).

10. The nucleic acid molecule of claim 5, wherein said nucleic acid molecule hybridizes under stringent conditions to a nucleotide sequence chosen from the group consisting of SEQ ID NOS: l , 3, 5, 7, 9, 1 1, 13, 15, 17, 19, 21, 23, 101, 103, 105, 107, 109, 1 12, 1 15, 1 17, 119, 121, 124, 135, 137, 139, 141, 143, 145, 147, 149, 151, 153, 155, 157, 159, 161, 163, 165, and 166, or a complement of said nucleotide sequence.

1 1. The nucleic acid molecule of claim 5, wherein the nucleic acid molecule comprises a nucleotide sequence selected from the group consisting of:

(a) a first nucleotide sequence comprising a coding sequence differing by one or more nucleotide sequences from a coding sequence encoding said amino acid sequence, provided that no more than 20% ofthe nucleotides in the coding sequence in said first nucleotide sequence differ from said coding sequence;

(b) an isolated second polynucleotide that is a complement ofthe first polynucleotide; and

(c) a nucleic acid fragment of (a) or (b).

12. A vector comprising the nucleic acid molecule of claim 1 1 .

13. The vector of claim 12, further comprising a promoter operably-linked to said nucleic acid molecule.

14. A cell comprising the vector of claim 12.

15. An antibody that binds immunospecifically to the polypeptide of claim 1.

16. The antibody of claim 15, wherein said antibody is a monoclonal antibody.

17. The antibody of claim 15, wherein the antibody is a humanized antibody.

18. A method for determining the presence or amount ofthe polypeptide of claim 1 in a sample, the method comprising:

(a) providing the sample;

(b) contacting the sample with an antibody that binds immunospecifically to the polypeptide; and

(c) determining the presence or amount of antibody bound to said polypeptide, thereby determining the presence or amount of polypeptide in said sample.

19. A method for determining the presence or amount ofthe nucleic acid molecule of claim 5 in a sample, the method comprising:

(a) providing the sample;

(b) contacting the sample with a probe that binds to said nucleic acid molecule; and

(c) determining the presence or amount ofthe probe bound to said nucleic acid molecule, thereby determining the presence or amount ofthe nucleic acid molecule in said sample.

20. The method of claim 19 wherein presence or amount ofthe nucleic acid molecule is used as a marker for cell or tissue type.

21. The method of claim 20 wherein the cell or tissue type is cancerous.

22. A method of identifying an agent that binds to a polypeptide of claim 1, the method comprising:

(a) contacting said polypeptide with said agent; and

(b) determining whether said agent binds to said polypeptide.

23. The method of claim 22 wherein the agent is a cellular receptor or a downstream effector.

24. A method for identifying an agent that modulates the expression or activity ofthe polypeptide of claim 1, the method comprising:

(a) providing a cell expressing said polypeptide;

(b) contacting the cell with said agent, and

(c) determining whether the agent modulates expression or activity of said polypeptide, whereby an alteration in expression or activity of said peptide indicates said agent modulates expression or activity of said polypeptide.

25. A method for modulating the activity ofthe polypeptide of claim 1, the method comprising contacting a cell sample expressing the polypeptide of said claim with a compound that binds to said polypeptide in an amount sufficient to modulate the activity ofthe polypeptide.

26. - A method of treating or preventing a MOLX-associated disorder, said method comprising administering to a subject in which such treatment or prevention is desired the polypeptide of claim 1 in an amount sufficient to treat or prevent said MOLX-associated disorder in said subject.

27. The method of claim 26 wherein the disorder is selected from the group consisting of cardiomyopathy and atherosclerosis.

28. The method of claim 26 wherein the disorder is related to cell signal processing and metabolic pathway modulation.

29. The method of claim 26, wherein said subject is a human.

30. A method of treating or preventing a MOLX-associated disorder, said method comprising administering to a subject in which such treatment or prevention is desired the nucleic acid of claim 5 in an amount sufficient to treat or prevent said MOLX-associated disorder in said subject.

31. The method of claim 30 wherein the disorder is selected from the group consisting of cardiomyopathy and atherosclerosis.

32. The method of claim 30 wherein the disorder is related to cell signal processing and metabolic pathway modulation.

33. The method of claim 30, wherein said subject is a human.

34. A method of treating or preventing a MOLX-associated disorder, said method comprising administering to a subject in which such treatment or prevention is desired the antibody of claim 15 in an amount sufficient to treat or prevent said MOLX-associated disorder in said subject.

35. The method of claim 34 wherein the disorder is diabetes.

36. The method of claim 34 wherein the disorder is related to cell signal processing and metabolic pathway modulation.

37. The method of claim 34, wherein the subject is a human.

38. A pharmaceutical composition comprising the polypeptide of claim 1 and a pharmaceutically-acceptable carrier.

39. A pharmaceutical composition comprising the nucleic acid molecule of claim 5 and a pharmaceutically-acceptable carrier.

40. A pharmaceutical composition comprising the antibody of claim 15 and a pharmaceutically-acceptable carrier.

41. A kit comprising in one or more containers, the pharmaceutical composition of claim 38.

42. A kit comprising in one or more containers, the pharmaceutical composition of claim 39.

43. A kit comprising in one or more containers, the pharmaceutical composition of claim 40.

44. A method for determining the presence of or predisposition to a disease associated with altered levels ofthe polypeptide of claim 1 in a first mammalian subject, the method comprising:

(a) measuring the level of expression ofthe polypeptide in a sample from the first mammalian subject; and (b) comparing the amount of said polypeptide in the sample of step (a) to the amount ofthe polypeptide present in a control sample from a second mammalian subject known not to have, or not to be predisposed to, said disease; wherein an alteration in the expression level ofthe polypeptide in the first subject as compared to the control sample indicates the presence of or predisposition to said disease.

45. The method of claim 44 wherein the predisposition is to cancers.

46. A method for determining the presence of or predisposition to a disease associated with altered levels ofthe nucleic acid molecule of claim 5 in a first mammalian subject, the method comprising:

(a) measuring the amount ofthe nucleic acid in a sample from the first mammalian subject; and

(b) comparing the amount of said nucleic acid in the sample of step (a) to the amount ofthe nucleic acid present in a control sample from a second mammalian subject known not to have or not be predisposed to, the disease; wherein an alteration in the level ofthe nucleic acid in the first subject as compared to the control sample indicates the presence of or predisposition to the disease.

47. The method of claim 46 wherein the predisposition is to a cancer.

48. A method of treating a pathological state in a mammal, the method comprising administering to the mammal a polypeptide in an amount that is sufficient to alleviate the pathological state, wherein the polypeptide is a polypeptide having an amino acid sequence at least 95% identical to a polypeptide comprising an amino acid sequence of at least one of SEQ ID NOS :2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 102, 104, 106, 108, 1 1 1, 1 14, 116, 118, 120, 123, 125, 136, 138, 140, 142, 144, 146, 148, 150, 152, 154, 156, 158, 160, 162, 164, and 167, or a biologically active fragment thereof.

49. A method of treating a pathological state in a mammal, the method comprising administering to the mammal the antibody of claim 15 in an amount sufficient to alleviate the pathological state.

50. A method for the screening of a candidate substance interacting with an olfactory receptor polypeptide selected from the group consisting of SEQ ID NOS:2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 102, 104, 106, 108, 11 1, 1 14, 1 16, 1 18, 120, 123, 125, 136, 138, 140, 142, 144, 146, 148, 150, 152, 154, 156, 158, 160, 162, 164, and 167, or fragments or variants thereof, comprises the following steps: a) providing a polypeptide selected from the group consisting ofthe sequences of SEQ ID NOS:2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 102, 104, 106, 108, 1 1 1, 1 14, 1 16, 1 18, 120, 123, 125, 136, 138, 140, 142, 144, 146, 148, 150, 152, 154, 156, 158, 160, 162, 164, and 167, or a peptide fragment or a variant thereof; b) obtaining a candidate substance; c) bringing into contact said polypeptide with said candidate substance; and d) detecting the complexes formed between said polypeptide and said candidate substance.

51. A method for the screening of ligand molecules interacting with an olfactory receptor polypeptide selected from the group consisting of SEQ ID NOS:2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 102, 104, 106, 108, 111, 114, 1 16, 1 18, 120, 123, 125, 136, 138, 140, 142, 144, 146, 148, 150, 152, 154, 156, 158, 160, 162, 164, and 167, wherein said method comprises: a) providing a recombinant eukaryotic host cell containing a nucleic acid encoding a polypeptide selected from the group consisting ofthe polypeptides comprising the amino acid sequences SEQ ID NOS:2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 102, 104, 106, 108, 1 1 1, 114, 116, 118, 120, 123, 125, 136, 138, 140, 142, 144, 146, 148, 150, 152, 154, 156, 158, 160, 162, 164, and 167; b) preparing membrane extracts of said recombinant eukaryotic host cell; c) bringing into contact the membrane extracts prepared at step b) with a selected ligand molecule; and d) detecting the production level of second messengers metabolites.

52. A method for the screening of ligand molecules interacting with an olfactory receptor polypeptide selected from the group consisting of SEQ ID NOS:2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 102, 104, 106, 108, 111, 114, 116, 1 18, 120, 123, 125, 136, 138, 140, 142, 144, 146, 148, 150, 152, 154, 156, 158, 160, 162, 164, and 167, wherein said method comprises: a) providing an adenovirus containing a nucleic acid encoding a polypeptide selected from the group consisting of polypeptides comprising the amino acid sequences SEQ ID NOS:2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 102, 104, 106, 108, 11 1, 1 14, 1 16, 1 18, 120, 123, 125, 136, 138, 140, 142, 144, 146, 148, 150, 152, 154, 156, 158, 160, 162, 164, and 167; b) infecting an olfactory epithelium with said adenovirus; c) bringing into contact the olfactory epithelium b) with a selected ligand molecule; and d) detecting the increase ofthe response to said ligand molecule.