CN112961864A - 突变的asxl3基因及应用 - Google Patents
突变的asxl3基因及应用 Download PDFInfo
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- CN112961864A CN112961864A CN202110217238.XA CN202110217238A CN112961864A CN 112961864 A CN112961864 A CN 112961864A CN 202110217238 A CN202110217238 A CN 202110217238A CN 112961864 A CN112961864 A CN 112961864A
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Abstract
本发明公开了突变的ASXL3cDNA,其与野生型ASXL3cDNA相比至少具有下列复合杂合突变:(c.2168C>G,c.5449C>G);其中,所述野生型ASXL3基因的cDNA序列如SEQ ID NO:1所示。本发明还公开了一些突变的ASXL3cDNA的应用。本发明还公开了突变的ASXL3基因。
Description
技术领域
本发明涉及分子遗传学领域,特别是涉及突变的ASXL3基因及应用。
背景技术
先天性心脏病(Congenital heart disease,CHD)是一种心脏形态、结构和功能异常疾病,其发病率为活产婴儿的6-8‰。最常见的相关症状是室间隔缺损(ventricularseptal defects,VSDs)、房间隔缺损和法洛四联症(tetralogy of Fallot,TOF)。先心病的病因包括有遗传因素和非遗传因素。一般地,散发性先心病的病例比较常见,但是也有一部分病例为家族性的,表现为孟德尔遗传,外显率可变。
对引起先心病致病基因的发现与检测,可加强对心脏发育的理解,为产前诊断提供指导。新近发展起来的下一代高通量测序技术(Next Generation Sequencing,NGS)能够直接在全基因组30亿个碱基范围内精确检测基因的变异位点,为探索和发现遗传病的致病基因提供技术便利和可行性。其中全外显子组测序(Whole exome sequencing,WES)以其经济、有效的优势已广泛应用于遗传病及复杂疾病的研究。随着WES的发展,将发现更多与先心病相关的基因,从而进一步深入了解该病的遗传原因。
目前,有研究表明,NKX2-5、GATA4和TBX1等基因突变与家族性先心病相关。
发明内容
基于此,有必要提供一种突变的ASXL3基因及应用。
本发明提供一种突变的ASXL3 cDNA,其与野生型ASXL3 cDNA相比至少具有下列复合杂合突变:(c.2168C>G,c.5449C>G);
其中,所述野生型ASXL3基因的cDNA序列如SEQ ID NO:1所示。
如本文中所使用的,术语“c.2168”是指cDNA序列的第2168位碱基(以起始密码子ATG的碱基A为第1位碱基),其中“c.”表示cDNA,数字“2168”表示第2168位碱基。本文中所使用的其他类似的术语,例如c.5449等,具有类似的含义。其中,c.2168C>G指的是cDNA的第2168位碱基由C突变为G;c.5449C>G指的是cDNA的第5449位碱基由C突变为G。
本发明还提供一种包含所述的突变的ASXL3 cDNA的载体。
本发明还提供一种包含所述的突变的ASXL3 cDNA的宿主细胞。
本发明还提供一种包含所述的突变的ASXL3 cDNA的非人类动物作为先天性心脏病动物模型的应用。
本发明还提供一种所述的突变的ASXL3 cDNA作为治疗先天性心脏病的药物靶点的应用。
本发明还提供一种特异性检测所述的突变的ASXL3 cDNA的诊断剂在制备用于诊断先天性心脏病的试剂或试剂盒中的应用。
在一些实施方案中,所述试剂包括引物或探针。
在一些实施方案中,所述试剂盒包括引物或探针。
在一些实施方案中,所述试剂用于检测ASXL3蛋白表达水平。
本发明还提供一种野生型ASXL3蛋白在制备用于治疗所述的突变的ASXL3 cDNA导致的先天性心脏病的试剂或试剂盒中的应用。
本发明还提供一种基因编辑试剂在制备用于治疗所述的突变的ASXL3 cDNA导致的先天性心脏病的试剂或试剂盒中的应用,所述基因编辑试剂包括能够纠正患者中所述的突变的ASXL3 cDNA对应的突变ASXL3基因而使所述突变ASXL3基因恢复为野生型ASXL3基因的试剂。
本发明还提供一种突变的ASXL3基因,其与野生型ASXL3基因相比,在cDNA水平上至少具有下列复合杂合突变:(c.2168C>G,c.5449C>G);
其中,所述野生型ASXL3基因的cDNA序列如SEQ ID NO:1所示。
本发明首次提供了人先天性心脏病的新致病基因ASXL3,该基因目前只报道可导致常染色体显性遗传模式的Bainbridge-Ropers综合征,发明人拓宽了该基因的疾病突变谱并提供了新的复合杂合致病突变(c.2168C>G,c.5449C>G)的检测方法,有望作为该病药物制备的靶点。
附图说明
图1为本发明一实施例的先天性心脏病家系超声心动图以及系谱图,其中,图1A为超声心动图,图1B为系谱图;
图2为本发明一实施例家系1的ASXL3基因突变位点sanger验证图,其中,图2A为2168位碱基,图2B为5449位碱基;
图3为本发明一实施例的细胞模型中复合杂合突变的生物学分析图,其中,图3A为载体mRNA的表达qPCR结果图,图3B为载体mRNA的表达western blot结果图,图3C为细胞生存能力图,图3D为流式细胞仪凋亡检测图;
图4为本发明一实施例的不同突变心脏结构变化的HE染色与Masson染色图;
图5为本发明一实施例的lncRNA和mRNAs的差异表达和功能分析;其中,图5A和图5B分别为lncRNA差异分析热图与火山图,图5C和图5D分别为mRNA差异分析热图与火山图,图5E为GO分析结果,图5F为KEGG富集分析结果。
具体实施方式
为了便于理解本发明,下面将参照相关附图对本发明进行更全面的描述。附图中给出了本发明的较佳实施例。但是,本发明可以以许多不同的形式来实现,并不限于本文所描述的实施例。相反地,提供这些实施例的目的是使对本发明的公开内容的理解更加透彻全面。
除非另有定义,本文所使用的所有的技术和科学术语与属于本发明的技术领域的技术人员通常理解的含义相同。本文中在本发明的说明书中所使用的术语只是为了描述具体的实施例的目的,不是旨在于限制本发明。
在本发明中,术语“突变”是指基因序列或DNA序列中一个或数个(例如几个)碱基的添加、缺失和/或置换。当用于描述基因所编码的产物或者蛋白质时,“突变”指的是所述蛋白质或编码产物中一个或数个(例如几个)氨基酸残基的添加、缺失和/或置换。
在本发明中,术语“杂合突变”是指突变仅存在于一对等位基因中的一个基因中。
在本发明中,术语“复合杂合突变”是指是指同一基因的不同位置出现2处或2处以上的杂合突变。
已有研究报道ASXL3基因突变可导致Bainbridge-Ropers综合征、肿瘤、小头畸形和全面发育迟缓。ASXL1和ASXL2基因作为ASXL3的同源基因,是心脏正常发育和维持心脏功能所必需的,但它们具体的致病机制尚不清楚。ASXL3的截断突变可导致常染色体显性遗传模式(以神经发育类症状为特征)的Bainbridge-Ropers综合征,但目前还没有研究数据表明ASXL3基因在心脏发育中的作用,以及ASXL3的致病变异在先心病发病机制中的作用。此外,ASXL3突变相关的下游靶点/效应物与先心病关系仍不清楚。
在本发明中,来自一个中国家庭的26w+胎儿和两个孩子被诊断为先心病,他们的父母目前没有发现心脏功能相关问题。发明人通过WES分析在该家系胎儿和2例患者中都发现了ASXL3基因的复合杂合突变c.2168C>G(p.Pro723Arg)和c.5449C>G(p.Pro1817Ala)。通过细胞实验发现此复合杂合突变在HL-1细胞中过表达,导致细胞凋亡增加,细胞存活率降低。构建小鼠模型发现突变影响小鼠的心脏结构和纤维化。RNA测序(RNA-seq)发现ASXL3复合杂合突变小鼠心脏组织有126个mRNAs表达下调,117个mRNAs表达上调相比野生型小鼠。ASXL3基因在心脏发育中起重要作用,可能通过影响与细胞凋亡和细胞增殖相关的mRNA的表达来调控心脏的发育。因此,综合以上包含5例样本(正常父母和三个患儿)的家系的结果提示,ASXL3基因复合杂合突变可导致先天性心脏病,并呈常染色体隐性遗传模式。
本发明首次提供了人先天性心脏病的新致病基因ASXL3,该基因目前只报道可导致常染色体显性遗传模式的Bainbridge-Ropers综合征,发明人拓宽了该基因的疾病突变谱并提供了新的复合杂合致病突变(c.2168C>G,c.5449C>G)的检测方法,有望作为该病药物制备的靶点。
本发明实施例提供一种突变的ASXL3 cDNA,其与野生型ASXL3 cDNA相比至少具有下列复合杂合突变:(c.2168C>G,c.5449C>G)。
其中,所述野生型ASXL3基因的cDNA序列如SEQ ID NO:1所示。
这里复合杂合突变指的是c.2168C>G,c.5449C>G同时突变并分别位于两条同源染色体上。
本发明首次提供了人先天性心脏病的新致病基因ASXL3,该基因目前只报道可导致常染色体显性遗传模式的Bainbridge-Ropers综合征,通过本申请的相关研究内容,发明人拓宽了该基因的疾病突变谱并提供了新的复合杂合致病突变(c.2168C>G,c.5449C>G)的检测方法,有望作为该病药物制备的靶点。
本发明实施例还提供一种包含所述的突变的ASXL3 cDNA的载体。
在一些实施方案中,所述载体可特别选自pcDNA;pTT(Durocher等,Nucleic AcidsResearch 2002,Vol 30,No.2);pTT3(具有额外的多克隆位点的pTT);pEFBOS(Mizushima,S.和Nagata,S.,(1990)Nucleic Acids Research Vol 18,No.17);pBV;pJV和pBJ。
本发明实施例还提供一种包含所述的突变的ASXL3 cDNA的宿主细胞。
在一些实施方案中,用本文所披露的载体转化宿主细胞。在一些实施方案中,宿主细胞为原核细胞。在一些实施方案中,宿主细胞为大肠杆菌(E.coli)。在一些实施方案中,宿主细胞为真核细胞。在一些实施方案中,真核细胞选自原生生物细胞、动物细胞(如哺乳动物细胞、啮齿动物、禽类细胞和昆虫细胞)、植物细胞和真菌细胞。在一些实施方案中,宿主细胞为哺乳动物细胞,包括但不限于CHO和COS;或为真菌细胞,如酵母细胞,例如酿酒酵母(Saccharomycescerevisiae);或为昆虫细胞如Sf9。本文所限定的宿主细胞为不具有发育全能型的细胞,不包括胚胎干细胞、受精卵等。
本发明实施例还提供一种包含所述的突变的ASXL3 cDNA的非人类动物作为先天性心脏病动物模型的应用。
在一些实施方案中,本文所述的非人类动物是啮齿类动物;在一些实施方案中,啮齿类动物为小鼠;在一些实施方案中,啮齿类动物为大鼠。在一些实施方案中,本文所述的小鼠选自129品系、BALB/C品系、C57BL/6品系和混合的129xC57BL/6品系;在某些实施方案中,小鼠选自C57BL/6品系。
本发明实施例还提供一种所述的突变的ASXL3 cDNA作为治疗先天性心脏病的药物靶点的应用。
本发明实施例还提供一种特异性检测所述的突变的ASXL3 cDNA的诊断剂在制备用于诊断先天性心脏病的试剂或试剂盒中的应用。
在一些实施方案中,所述试剂包括引物或探针。
在一些实施方案中,所述试剂盒包括引物或探针。
在一些实施方案中,该引物或者探针能够与ASXL3的突变位点特异性结合。使用该引物或和探针对待测样品进行PCR,如果能够扩增出产物,这说明该样品存在ASXL3的突变,如果无法扩增出产物,则说明ASXL3未突变或者ASXL3的c.2168C,c.5449C位点未突变。
在一些实施方案中,所述试剂用于检测ASXL3蛋白表达水平。
本发明还提供一种野生型ASXL3蛋白在制备用于治疗所述的突变的ASXL3 cDNA导致的先天性心脏病的试剂或试剂盒中的应用。
特别地,本发明的治疗试剂野生型ASXL3蛋白施用方式可以是传统的施用途径,包括静脉滴注、肌肉注射、***、口服、口腔、舌下、眼球、局部、肠胃外、直肠、叶鞘内、内胞浆网槽内、腹股沟、膀胱内、局部(如,粉剂、药膏或滴剂),或鼻腔途径,但不仅局限于此。
本发明还提供一种突变的ASXL3基因,其与野生型ASXL3基因相比,在cDNA水平上至少具有下列复合杂合突变:(c.2168C>G,c.5449C>G);
其中,所述野生型ASXL3基因的cDNA序列如SEQ ID NO:1所示。
这里突变的ASXL3基因指的是经转录得到mRNA,该mRNA经反转录能够得到上述突变的cDNA的核苷酸序列,该突变的ASXL3基因可包含或者不包含内含子。
该突变的ASXL3基因具有与上述任一实施例的突变的ASXL3 cDNA相同的应用,即,包含该突变的ASXL3基因的载体。包含该突变的ASXL3基因的宿主细胞。包含该突变的ASXL3基因的非人类动物作为先天性心脏病动物模型的应用。特异性检测该突变的ASXL3基因的诊断剂在制备用于诊断先天性心脏病的试剂或试剂盒中的应用。野生型ASXL3蛋白在制备用于治疗该突变的ASXL3基因导致的先天性心脏病的试剂或试剂盒中的应用等等。
本发明还提供一种基因编辑试剂在制备用于治疗所述的突变的ASXL3 cDNA对应的突变的ASXL3基因导致的先天性心脏病的试剂或试剂盒中的应用,所述基因编辑试剂包括能够纠正患者中所述的突变的ASXL3 cDNA对应的突变ASXL3基因而使所述突变ASXL3基因恢复为野生型ASXL3基因的试剂。
在一些实施方案中,采用常用的基因编辑方法将野生型ASXL3蛋白基因替换突变的ASXL3基因或者直接敲入野生型ASXL3蛋白基因。基因编辑方法例如为CRISPR/Cas9技术。Crispr-Cas9***所需的基因编辑试剂例如包括sgRNA和Cas9酶等。
本发明首次提供了人先天性心脏病的新致病基因ASXL3,并提供了新的复合杂合致病突变(c.2168C>G,c.5449C>G)的检测方法。通过HL-1细胞和小鼠模型实验,发现ASXL3基因新的复合杂合突变导致ASXL3蛋白表达出错,影响细胞存活,并导致心脏结构异常。通过RNA-seq在ASXL3复合杂合突变小鼠心脏中发现243个差异表达的mRNAs,这些差异表达的mRNAs可能在细胞凋亡和细胞增殖过程中发挥作用。通过qPCR和Western blot在突变小鼠中证实了表达上调的Ezh2、Slc6a4和Socs3的mRNA或蛋白。因此,ASXL3复合杂合突变可导致先天性心脏病,呈常染色体隐性遗传模式。本发明提供的ASXL3基因特定突变增加了该病致病基因突变谱,可以为先天性心脏病致病机理的解析、致病基因检测、治疗药物的开发以及针对性治疗等提供依据和奠定基础。
1、样本收集
发明人收集到三例患有先天性心脏病的兄妹,他们的父母心脏功能正常,其家系图如图1B,本次发明经广州市妇女儿童医疗中心伦理委员会批准,坚持1964年《赫尔辛基宣言》和其后修订内容中制定的标准。所有参与个体都由本人或他们的监护人签署了知情同意书。收集了包括年龄、性别和临床症状在内的临床信息。除了26w+胎儿采集其脐带血,其他家系成员采集外周血;先证者胎儿P5(26w+),与P3(10岁女孩)和P4(7岁男孩)来自同一父母,均被确定为先心病。超声心动图结果显示,三个患者都有心脏发育异常(图1A)。P5患儿产前超声检查发现室间隔缺损VSD、大动脉转位、先天性角膜炎;P3法洛四联症,血管瘤和斜视;P4法洛四联症,眼底白斑,尿道下裂,双手有骨纤维瘤;父母心电图及超声心动图示心脏功能及结构正常。该家系表现为常染色体隐性遗传。采用荧光定量PCR(QF-PCR)对该家系5个成员常见的非整倍体进行快速产前诊断。采用染色体G显带核型分析诊断染色体水平异常。QF-PCR和G带核型分析未发现有异常。
2、微阵列分析(chromosome microarray analysis,CMA)
所有样本DNA的提取使用QIAamp DNA Blood Mini Kit试剂盒,基因组DNA杂交微阵列芯片使用Human CNV Association Microarray Kit(安捷伦,美国加利福尼亚)。芯片数据分析使用Genomic Workbench软件(安捷伦)。拷贝数变异(CNVs)结果致病性的判定通过与文献以及数据库的比较,比如人群多态性数据库DGV、病例数据库DECIPHER、基因剂量效应数据库ClinGen、人类孟德尔遗传在线数据库OMIM等。
通过微阵列分析(CMA)技术对该家系胎儿及患者进行检测,结果未检出明确致病性微缺失或微重复变异。
3、全外显子测序
发明人采用SureSelect XT Human All Exon 50Mb V5 Kit(安捷伦)捕获芯片对所有的DNA样本杂交获取目标区域序列,在Illumina HiSeq 2500测序仪上进行双末端150bp测序。测序后获得的原始数据使用fastp(V0.20)进行原始数据质控,去除含有接头或者低质量的reads,将质控后的clean data利用BWA(V0.7.17)比对到人类参考基因组GRCH37(hg19),利用Samtools(V1.9)以及Picard软件对比对后的数据排序以及标记重复序列,最后使用GATK(V3.8)的HaplotypeCaller模块检测样本的变异信息;对得到的初始变异结果进行过滤留下高质量的信息,去掉条件满足以下之一的变异:突变总深度低于10,基因型质量值低于50以及比对质量值低于30。变异的注释使用VEP(Variant EffectPredictor),同时注释疾病数据库,人群频率数据库,危害性或保守型预测软件以及变异位点数据库等信息;群体数据库包括千人基因组(1000genomics)、gnomAD和实验室的本地频率数据库;危害性或保守型预测软件包括SIFT,Polyphen2_HDIV,REVEL,MutationTaster以及MetaSVM等,变异位点数据库ClinVar和HGMD以及疾病数据库OMIM,Orphanet,MedGen,DDG2P等。
通过对上述所有家系成员的数据分析,优先关注可能影响蛋白功能的编码区以及剪切区域,同时群体数据频率小于0.05的变异,结合家系共分离信息,发明人主要考虑了三种遗传模式:de novo突变的显性、隐性纯合变异和隐性复合杂合变异。最后发明人找到ASXL3基因的复合杂合突变。Sanger测序该复合杂合突变在胎儿和两个孩子中都得到验证,其中c.2168C>G(p.Pro723Arg)遗传自父亲,c.5449C>G(p.Pro1817Ala)遗传自母亲(表1)。
家系的病例结果提示,ASXL3基因的复合杂合突变可导致先天性心脏病的发生,并呈常染色体隐性遗传模式,而且可以由不同的ASXL3致病变异造成。
4、ASXL3基因复合杂合致病位点的扩增与sanger测序验证
ASXL3基因包括12个外显子Exons,c.2168C>G突变位于Exon 11,c.5449C>G突变位于Exon 12,设计引物,分别在先证者及家系所有成员内通过PCR扩增,产物纯化获得ASXL3基因突变所在序列,然后sanger测序,根据序列测定结果判断位点属于突变型还是野生型。
1)DNA提取:所有样本DNA的提取使用QIAamp DNA Blood Mini Kit试剂盒。
2)引物设计及PCR反应:引物设计参考人类基因组参考序列Hg19/GRCH37,设计突变位点特异性引物,具体见下表1。
表1
引物 | 上游引物 | SEQ ID NO | 下游引物 | SEQ ID NO |
c.2168C>G | ctgtaccagcctgccttctc | 2 | tgctgatgtgccattctctc | 3 |
c.5449C>G | aatcaacaggcttccattgc | 4 | taccagcgtcagtgtggaag | 5 |
按以下配比分别配置各基因组DNA样本的PCR反应体系:
反应体系:33.1μL
将各PCR反应体系按照以下表2的反应条件分别进行PCR反应:
表2
3)sanger测序
将上述PCR扩增产物直接进行sanger测序(ABI 3730 DNA Analyzer)。
通过验证,ASXL3基因致病突变位点信息见表2,Sanger测序验证峰图分别见图2(家系1)。
表2 ASXL3基因突变位点
野生型ASXL3基因的cDNA具有如下所示的核苷酸序列,6747nt,单下划线及加粗标注为家系1复合杂合突变位置(SEQ ID NO:1):
其编码的蛋白具有如下所示的氨基酸序列,2248aa,单下划线及加粗标注为家系1复合杂合突变位置(SEQ ID NO:6):
5、细胞模型中复合杂合突变的生物学分析
发明人构建了3个载体,包括一个野生型载体,一个ASXL3过表达载体,以及一个含有ASXL3基因复合杂合突变(P723R+P1817A)载体,分别将这些载体转染HL-1细胞构建LV003、LV003-ASXL3以及LV003-ASXL3(P723R+P1817A)组别。载体mRNA的表达使用qPCR和western blot检测,结果显示相比于LV003组,LV003-ASXL3(P723R+P1817A)和LV003-ASXL3组的ASXL3的表达显著增加(图3A,B),细胞生存能力显著提高在72h(图3C)。流式细胞仪凋亡检测发现LV003组与LV003-ASXL3组之间没有明显的差异,但是LV003-ASXL3(P723R+P1817A)组的凋亡水平明显升高(图3D)。
6、构建ASXL3复合杂合突变小鼠模型
提供ASXL3基因复合杂合突变(c.2168C>G和c.5449C>G)小鼠,由Cyagen(美国)构建提供。小鼠分成四组:(P723R)-/-(P1817A)-/-,(P723R)+/-(P1817A)-/-,(P723R)-/-(P1817A)+/-,和(P723R)+/-(P1817A)+/-,这些小鼠是由ASXL3基因(P723R)+/-(P1817A)-/-和(P723R)-/-(P1817A)+/-突变小鼠杂交产生,通过逆转录PCR验证确认。收集4-6周龄的野生型小鼠及杂交后代小鼠的心脏组织。所有动物研究遵循欧洲议会2010/63/EU关于保护动物用于科学研究的指南或美国国立卫生研究院的指南。qPCR和western blot用以检测ASXL3 mRNA和蛋白的表达水平。HE染色显示复合杂合突变组小鼠心肌致密度不完全,左心室肌呈海绵状改变,病变区室明显增大,心肌细胞密度降低(图4A)。在(P723R)+/-(P1817A)+/-小鼠中观察到纤维化增加(图4B)。与野生型小鼠相比,当ASXL3基因发生突变,这些小鼠的心脏结构也发生了变化;特别是复合杂合突变组表现出明显的心肌肥厚。同样,心脏结构超声扫描的分析也显示,ASXL3基因突变小鼠心脏结构发生变化,尤其在在ASXL3复合杂合突变小鼠中最为明显。
对复合杂合突变小鼠肌肉注射野生型ASXL3蛋白之后,发现小鼠的心脏结构得到改善。
发明人通过RNA-seq对来源于野生型小鼠和ASXL3复合杂合突变小鼠的心脏组织测序,发现243个mRNAs异常表达在ASXL3复合杂合突变小鼠中相比于野生型小鼠,其中有126个mRNAs表达下调,117个mRNAs表达上调(图5A,5B,5C,5D)。GO分析显示复合杂合突变小鼠相关的mRNAs主要分布在细胞增殖和细胞死亡方面(图5E)。KEGG富集分析显示这些mRNAs主要富集在PI3K-Akt信号通路,肿瘤坏死因子TNF信号通路,心肌细胞的肾上腺素能,催产素信号通路,Jak-STAT信号通路,Rap1信号通路以及MAPK信号通路中(图5F),因此ASXL3复合杂合突变可能通过这些途径导致心脏发育异常。选取的6种mRNAs(Plod3、Suv39h1、Ezh2、Fos、Slc6a4和Socs3)的表达通过qPCR和western blot得到验证,证实了ASXL3、Ezh2、Slc6a4和Socs3在mRNA表达和蛋白水平上存在显著差异,因此,这些mRNAs可能参与心脏相关功能,调节代谢途径,诱导抑制细胞增殖,增加细胞凋亡。
以上所述实施例的各技术特征可以进行任意的组合,为使描述简洁,未对上述实施例中的各个技术特征所有可能的组合都进行描述,然而,只要这些技术特征的组合不存在矛盾,都应当认为是本说明书记载的范围。
以上所述实施例仅表达了本发明的几种实施方式,其描述较为具体和详细,但并不能因此而理解为对发明专利范围的限制。应当指出的是,对于本领域的普通技术人员来说,在不脱离本发明构思的前提下,还可以做出若干变形和改进,这些都属于本发明的保护范围。因此,本发明专利的保护范围应以所附权利要求为准。
序列表
<110> 广州市妇女儿童医疗中心
<120> 突变的ASXL3基因及应用
<160> 6
<170> SIPOSequenceListing 1.0
<210> 1
<211> 6747
<212> DNA
<213> Homo sapiens
<400> 1
atgaaagaca agaggaagaa gaaggaccgc acctgggccg aggctgcccg cctggcacta 60
gaaaaacacc ccaactcacc aatgacagca aagcagatat tggaagtcat tcagaaagaa 120
gggttaaaag aaacaagtgg aacctctcca ttagcctgtc tgaatgcaat gcttcacact 180
aacactcgaa taggggatgg aacattcttc aaaatccctg gaaagtcagg cctctatgct 240
ctcaaaaaag aggagtcgtc atgcccagca gatggcacgt tggatttagt ctgtgaatct 300
gaattggatg gtacagatat ggccgaggca aatgcccatg gagaagaaaa tggagtttgt 360
tcgaagcagg taactgatga agcatcttcc actcgagatt caagccttac taacacagca 420
gtgcaaagca agttagtgtc ttccttccag cagcacacca aaaaggctct taaacaggct 480
ttgaggcagc agcagaaaag aagaaatgga gtctcaatga tggtaaacaa gactgttcct 540
cgtgttgttt tgacaccatt aaaggtgtct gatgagcagt cggattcgcc ttcaggatct 600
gaatctaaaa atggtgaagc agacagttca gataaagaaa tgaaacatgg gcaaaaatct 660
cccactggaa aacaaacaag tcagcactta aaacgattaa aaaagtctgg tttagggcac 720
ttgaaatgga ccaaagctga ggacattgac atagaaaccc caggatctat tcttgtcaac 780
actaacttga gggcattaat aaataaacat acgtttgctt ccttacctca gcattttcaa 840
caatacctcc tgcttttgct cccagaagtg gataggcaga tgggaagtga tggaatttta 900
cgcctcagta cttcagctct aaataatgaa ttctttgcat atgcagcaca agggtggaaa 960
cagcgactgg cagaaggaga gtttacccca gaaatgcagt tgcggataag gcaagaaatt 1020
gagaaggaaa agaaaacaga accttggaaa gaaaaattct ttgagaggtt ttatggagaa 1080
aagctgggca tgtcaagaga ggaatctgtg aagctcacta ctggaccaaa caacgctgga 1140
gctcaaagta gttcttcatg tgggacttct ggccttccag tttctgcaca gacagccttg 1200
gcagaacaac agccaaaaag catgaaaagc ccagcttctc cagagcctgg tttctgtgct 1260
actctttgcc ctatggtaga aattccacct aaagatataa tggcagaatt ggagtcagag 1320
gatatcttga tccctgaaga atctgtaatt caggaggaaa ttgcagaaga ggtagagact 1380
agtatctgtg aatgccagga tgaaaatcat aagacaatac ctgaattttc tgaggaggct 1440
gaaagtctaa ccaattctca tgaagaaccc caaatagcac ctcctgaaga taacttggaa 1500
tcctgtgtta tgatgaatga tgttttagaa actttgcctc atattgaagt taagatagaa 1560
gggaagtcag aatcacccca ggaagaaatg acagttgtta tcgatcagtt agaagtctgt 1620
gactctctta ttccttccac ttcatctatg actcatgtca gtgacacaga acataaggag 1680
tcagaaactg cagtagagac cagtaccccc aaaataaaaa cagggtcatc ttctctagaa 1740
ggccagtttc caaatgaagg aattgctata gatatggagc tacagagtga ccctgaagaa 1800
cagctttcag aaaatgcctg catctctgaa acgtcctttt cttctgagag cccagaggga 1860
gcctgtacca gcctgccttc tccaggaggg gaaacacagt ccacatcaga agaatcatgt 1920
actccagcct cccttgagac aacattttgt tctgaggtat ctagcactga aaatacagac 1980
aaatacaacc agagaaattc cactgatgaa aactttcatg catctttgat gtcagaaata 2040
tctccaatat ccacttcacc tgaaatatca gaagcatctc ttatgtccaa cttaccatta 2100
acatctgaag catcaccagt atccaactta cctttaacat cagaaacctc accgatgtct 2160
gacttacctt taacatcaga aacttcttca gtgtcttcca tgcttctcac ctctgagacc 2220
acttttgtat ccagtttgcc acttccttca gaaacatctc caatttccaa ctcttccata 2280
aatgagagaa tggcacatca gcaaagaaag tcaccttctg tatctgaaga gccactctcc 2340
ccgcagaaag atgagtcttc cgccactgcc aaacctctgg gagagaacct tacctcccag 2400
cagaagaatc tgtctaatac tcccgaaccc atcataatga gttcttcttc cattgctcct 2460
gaagcatttc cgtctgaaga tttgcacaat aagaccctga gtcagcaaac ctgtaaatca 2520
catgttgaca ctgagaagcc ctaccctgct tcaattccag aacttgcttc tactgaaatg 2580
ataaaagtta aaaatcatag cgtcctgcaa agaacagaaa aaaaagtgtt accttcacca 2640
ttggaattat ctgtcttttc tgaagggaca gataataagg gaaatgagct tccatctgct 2700
aaattacagg acaagcaata tatctcatca gtggataagg ctccattttc agaaggctct 2760
agaaataaaa cacataagca agggagtaca cagagtcggt tagaaacctc acatacttcc 2820
aagtcatcag agccctccaa gtcacctgat gggataagaa atgaaagtag agattcagag 2880
atatcaaaga gaaaaactgc agagcaacac agctttggaa tctgtaagga aaagagagct 2940
aggatagaag atgatcagtc aacccggaac atatcatcta gcagcccacc tgagaaagaa 3000
cagcctccca gagaggaacc aagggttccc cctctcaaga ttcagctttc caaaattggg 3060
ccacctttta taatcaagag ccaaccagtc tccaaacctg agtctcgagc atccactagc 3120
acatctgtca gtggcgggag gaacacagga gccaggaccc tcgcagatat caaggcccgg 3180
gcccaacaag ctcgggccca gcgagaggct gctgcagctg ctgctgtggc tgctgcagcg 3240
agcattgtct ctggagccat gggaagtcca ggagagggtg gaaagacgag aactctggca 3300
cacatcaaag agcagacaaa ggctaagctc tttgcaaagc atcaagctcg agcccatctc 3360
ttccagacct ctaaagagac ccggttgcct cctccgctca gctcaaagga agggcctcca 3420
aacttagaag tctcttctac ccctgaaaca aaaatggaag gttcgactgg tgtcattatt 3480
gtcaatccaa actgtagatc tcctagcaac aagtctgccc acctccggga gaccaccact 3540
gtactacagc agtctcttaa cccaagtaaa cttccagaaa ctgccactga cttatctgtg 3600
catagttctg atgaaaacat acctgtgtca catttatctg agaaaattgt ttcatctacc 3660
tcttctgaaa atagcagtgt gcccatgctt tttaataaaa attctgtccc tgtatctgtt 3720
tgcagcactg ctatatcggg agcaattaaa gaacatccct ttgtgagttc tgttgataaa 3780
tcctctgtcc taatgtctgt tgacagtgca aacactacaa tttctgcttg taatataagc 3840
atgttaaaaa ccatccaggg aactgacact ccatgcatag ccattatacc aaaatgtatt 3900
gaaagcactc ccatttcagc cactacagag ggctccagca tatcaagctc catggatgat 3960
aagcagttac taatatcaag cagcagtgct agtaacttag tctccactca gtacacctct 4020
gtgccaactc cctccatcgg aaacaatttg ccaaacctct ccactagctc tgtcttgatt 4080
cccccaatgg gaattaacaa cagatttcct tctgagaaga tagccatacc tgggagtgaa 4140
gaacaggcca ctgtatccat gggtaccact gtgagagcag ccctcagctg cagtgattct 4200
gtagcggtca cagactctct ggttgcacac ccgaccgtcg caatgtttac tggaaacatg 4260
ctgacaataa actcttatga tagtcctccc aagttaagtg ctgaaagctt ggacaaaaat 4320
tcagggcctc gaaacagggc agataattct ggaaaacctc agcaaccacc agggggcttt 4380
gcaccagcag ccataaaccg atcaattccg tgtaaagtca tcgttgacca cagcaccacg 4440
ctgacctcca gtttgtctct gactgtctcc gttgaaagct cagaagccag cttggacctg 4500
cagggcagac cagtgaggac agaggcatcc gtacagcccg tggcgtgtcc tcaggtgtct 4560
gtgattagca ggcctgagcc agttgccaac gaaggtatag atcacagttc cactttcatt 4620
gctgcttcgg cagcaaaaca agacagtaaa acattgccgg ccacctgcac aagtctccga 4680
gaattacccc ttgttccaga taaattaaat gagccgactg ctcccagtca taactttgct 4740
gagcaggcac gtggcccagc tcctttcaaa agtgaagcag acacaacctg tagcaatcag 4800
tataacccaa gtaaccggat ttgctggaat gatgatggga tgaggagcac aggacagcct 4860
ctggttactc actcgggttc aagtaaacaa aaagaatatc tagagcaaag ctgtccaaag 4920
gctatcaaaa ctgaacatgc caactacttg aacgtgtcag aacttcatcc caggaatctt 4980
gtaacaaatg ttgctcttcc tgtgaaatct gaacttcacg aagcagacaa gggctttaga 5040
atggacactg aagacttccc tggccctgag ctgcctcctc cggctgcaga gggagcctct 5100
agtgtacaac aaacacagaa catgaaagct tccacctcaa gtcccatgga agaggctatt 5160
tccttggcta ccgatgccct gaagagagtc cctggtgcag ggagctcagg ctgtcgtctg 5220
tcctctgtgg aggctaacaa tccgctggtg acgcagttac tacagggcaa cctgcctttg 5280
gaaaaagtgt tgccacagcc cagattggga gccaagcttg aaatcaacag gcttccattg 5340
cctcttcaaa ctacctcagt gggtaaaaca gcaccagaga gaaacgttga aattccgccc 5400
agctctccaa atccagatgg taagggctac ttggcaggga ctctggcacc actccaaatg 5460
agaaagcgag aaaaccaccc caaaaagaga gtagctagga ctgtaggaga acacactcaa 5520
gttaaatgtg aaccaggaaa attgttggtg gagccagatg ttaaaggggt gccttgtgtc 5580
atcagttccg gcatcagtca gctaggacac agccagccat ttaagcaaga atggctaaac 5640
aagcactcca tgcagaacag aattgttcac agccctgagg tcaaacagca aaagcggctg 5700
ctcccctcgt gtagcttcca gcagaaccta tttcatgttg acaagaatgg cggcttccac 5760
actgacgctg gtacctcaca cagacagcag ttttaccaaa tgcctgtggc tgccaggggc 5820
cccattccta ctgcagctct gttacaggcc tcttccaaga ccccagtggg gtgtaatgca 5880
tttgccttca acaggcatct tgaacagaag ggattgggag aggttagtct ttcctcagca 5940
cctcaccagc taaggttagc caacatgtta tcccccaata tgcccatgaa agaaggtgat 6000
gaggtgggag gcactgcaca cacaatgcca aacaaagcac tagtacatcc gccgccgcca 6060
ccgcctcccc ctccccctcc acccttggct ttgcccccgc ctcccccccc accacctccg 6120
ctacctccac ctctccctaa tgcagaagtc ccatctgatc aaaaacaacc tccagttacc 6180
atggaaacca ctaagagact tagttggcca cagtccacgg gcatatgtag caatataaaa 6240
tcggaacctc tttcttttga ggaaggttta agcagcagct gtgaactggg catgaaacaa 6300
gtttcctatg accagaatga aatgaaagaa cagttaaaag cattcgcgct aaaaagtgca 6360
gatttctctt cctatttgct ttctgagcca caaaagcctt ttacccaatt agctgctcag 6420
aaaatgcagg tgcagcaaca acagcagctc tgtggaaatt atccaacaat acactttggt 6480
agcacgagtt tcaaaagggc agcatctgca attgaaaagt ccattgggat tttgggaagt 6540
ggctccaatc ctgccacagg cttgtctggt cagaacgctc agatgcccgt tcagaacttt 6600
gccgacagca gcaatgcaga tgaattggaa ctgaaatgct cttgccggct gaaagccatg 6660
attgtgtgca aaggctgtgg ggccttctgc catgacgact gcataggtcc ttcaaaactt 6720
tgtgtagcat gcctggttgt acgataa 6747
<210> 2
<211> 20
<212> DNA
<213> Artificial Sequence
<400> 2
ctgtaccagc ctgccttctc 20
<210> 3
<211> 20
<212> DNA
<213> Artificial Sequence
<400> 3
tgctgatgtg ccattctctc 20
<210> 4
<211> 20
<212> DNA
<213> Artificial Sequence
<400> 4
aatcaacagg cttccattgc 20
<210> 5
<211> 20
<212> DNA
<213> Artificial Sequence
<400> 5
taccagcgtc agtgtggaag 20
<210> 6
<211> 2248
<212> PRT
<213> Homo sapiens
<400> 6
Met Lys Asp Lys Arg Lys Lys Lys Asp Arg Thr Trp Ala Glu Ala Ala
1 5 10 15
Arg Leu Ala Leu Glu Lys His Pro Asn Ser Pro Met Thr Ala Lys Gln
20 25 30
Ile Leu Glu Val Ile Gln Lys Glu Gly Leu Lys Glu Thr Ser Gly Thr
35 40 45
Ser Pro Leu Ala Cys Leu Asn Ala Met Leu His Thr Asn Thr Arg Ile
50 55 60
Gly Asp Gly Thr Phe Phe Lys Ile Pro Gly Lys Ser Gly Leu Tyr Ala
65 70 75 80
Leu Lys Lys Glu Glu Ser Ser Cys Pro Ala Asp Gly Thr Leu Asp Leu
85 90 95
Val Cys Glu Ser Glu Leu Asp Gly Thr Asp Met Ala Glu Ala Asn Ala
100 105 110
His Gly Glu Glu Asn Gly Val Cys Ser Lys Gln Val Thr Asp Glu Ala
115 120 125
Ser Ser Thr Arg Asp Ser Ser Leu Thr Asn Thr Ala Val Gln Ser Lys
130 135 140
Leu Val Ser Ser Phe Gln Gln His Thr Lys Lys Ala Leu Lys Gln Ala
145 150 155 160
Leu Arg Gln Gln Gln Lys Arg Arg Asn Gly Val Ser Met Met Val Asn
165 170 175
Lys Thr Val Pro Arg Val Val Leu Thr Pro Leu Lys Val Ser Asp Glu
180 185 190
Gln Ser Asp Ser Pro Ser Gly Ser Glu Ser Lys Asn Gly Glu Ala Asp
195 200 205
Ser Ser Asp Lys Glu Met Lys His Gly Gln Lys Ser Pro Thr Gly Lys
210 215 220
Gln Thr Ser Gln His Leu Lys Arg Leu Lys Lys Ser Gly Leu Gly His
225 230 235 240
Leu Lys Trp Thr Lys Ala Glu Asp Ile Asp Ile Glu Thr Pro Gly Ser
245 250 255
Ile Leu Val Asn Thr Asn Leu Arg Ala Leu Ile Asn Lys His Thr Phe
260 265 270
Ala Ser Leu Pro Gln His Phe Gln Gln Tyr Leu Leu Leu Leu Leu Pro
275 280 285
Glu Val Asp Arg Gln Met Gly Ser Asp Gly Ile Leu Arg Leu Ser Thr
290 295 300
Ser Ala Leu Asn Asn Glu Phe Phe Ala Tyr Ala Ala Gln Gly Trp Lys
305 310 315 320
Gln Arg Leu Ala Glu Gly Glu Phe Thr Pro Glu Met Gln Leu Arg Ile
325 330 335
Arg Gln Glu Ile Glu Lys Glu Lys Lys Thr Glu Pro Trp Lys Glu Lys
340 345 350
Phe Phe Glu Arg Phe Tyr Gly Glu Lys Leu Gly Met Ser Arg Glu Glu
355 360 365
Ser Val Lys Leu Thr Thr Gly Pro Asn Asn Ala Gly Ala Gln Ser Ser
370 375 380
Ser Ser Cys Gly Thr Ser Gly Leu Pro Val Ser Ala Gln Thr Ala Leu
385 390 395 400
Ala Glu Gln Gln Pro Lys Ser Met Lys Ser Pro Ala Ser Pro Glu Pro
405 410 415
Gly Phe Cys Ala Thr Leu Cys Pro Met Val Glu Ile Pro Pro Lys Asp
420 425 430
Ile Met Ala Glu Leu Glu Ser Glu Asp Ile Leu Ile Pro Glu Glu Ser
435 440 445
Val Ile Gln Glu Glu Ile Ala Glu Glu Val Glu Thr Ser Ile Cys Glu
450 455 460
Cys Gln Asp Glu Asn His Lys Thr Ile Pro Glu Phe Ser Glu Glu Ala
465 470 475 480
Glu Ser Leu Thr Asn Ser His Glu Glu Pro Gln Ile Ala Pro Pro Glu
485 490 495
Asp Asn Leu Glu Ser Cys Val Met Met Asn Asp Val Leu Glu Thr Leu
500 505 510
Pro His Ile Glu Val Lys Ile Glu Gly Lys Ser Glu Ser Pro Gln Glu
515 520 525
Glu Met Thr Val Val Ile Asp Gln Leu Glu Val Cys Asp Ser Leu Ile
530 535 540
Pro Ser Thr Ser Ser Met Thr His Val Ser Asp Thr Glu His Lys Glu
545 550 555 560
Ser Glu Thr Ala Val Glu Thr Ser Thr Pro Lys Ile Lys Thr Gly Ser
565 570 575
Ser Ser Leu Glu Gly Gln Phe Pro Asn Glu Gly Ile Ala Ile Asp Met
580 585 590
Glu Leu Gln Ser Asp Pro Glu Glu Gln Leu Ser Glu Asn Ala Cys Ile
595 600 605
Ser Glu Thr Ser Phe Ser Ser Glu Ser Pro Glu Gly Ala Cys Thr Ser
610 615 620
Leu Pro Ser Pro Gly Gly Glu Thr Gln Ser Thr Ser Glu Glu Ser Cys
625 630 635 640
Thr Pro Ala Ser Leu Glu Thr Thr Phe Cys Ser Glu Val Ser Ser Thr
645 650 655
Glu Asn Thr Asp Lys Tyr Asn Gln Arg Asn Ser Thr Asp Glu Asn Phe
660 665 670
His Ala Ser Leu Met Ser Glu Ile Ser Pro Ile Ser Thr Ser Pro Glu
675 680 685
Ile Ser Glu Ala Ser Leu Met Ser Asn Leu Pro Leu Thr Ser Glu Ala
690 695 700
Ser Pro Val Ser Asn Leu Pro Leu Thr Ser Glu Thr Ser Pro Met Ser
705 710 715 720
Asp Leu Pro Leu Thr Ser Glu Thr Ser Ser Val Ser Ser Met Leu Leu
725 730 735
Thr Ser Glu Thr Thr Phe Val Ser Ser Leu Pro Leu Pro Ser Glu Thr
740 745 750
Ser Pro Ile Ser Asn Ser Ser Ile Asn Glu Arg Met Ala His Gln Gln
755 760 765
Arg Lys Ser Pro Ser Val Ser Glu Glu Pro Leu Ser Pro Gln Lys Asp
770 775 780
Glu Ser Ser Ala Thr Ala Lys Pro Leu Gly Glu Asn Leu Thr Ser Gln
785 790 795 800
Gln Lys Asn Leu Ser Asn Thr Pro Glu Pro Ile Ile Met Ser Ser Ser
805 810 815
Ser Ile Ala Pro Glu Ala Phe Pro Ser Glu Asp Leu His Asn Lys Thr
820 825 830
Leu Ser Gln Gln Thr Cys Lys Ser His Val Asp Thr Glu Lys Pro Tyr
835 840 845
Pro Ala Ser Ile Pro Glu Leu Ala Ser Thr Glu Met Ile Lys Val Lys
850 855 860
Asn His Ser Val Leu Gln Arg Thr Glu Lys Lys Val Leu Pro Ser Pro
865 870 875 880
Leu Glu Leu Ser Val Phe Ser Glu Gly Thr Asp Asn Lys Gly Asn Glu
885 890 895
Leu Pro Ser Ala Lys Leu Gln Asp Lys Gln Tyr Ile Ser Ser Val Asp
900 905 910
Lys Ala Pro Phe Ser Glu Gly Ser Arg Asn Lys Thr His Lys Gln Gly
915 920 925
Ser Thr Gln Ser Arg Leu Glu Thr Ser His Thr Ser Lys Ser Ser Glu
930 935 940
Pro Ser Lys Ser Pro Asp Gly Ile Arg Asn Glu Ser Arg Asp Ser Glu
945 950 955 960
Ile Ser Lys Arg Lys Thr Ala Glu Gln His Ser Phe Gly Ile Cys Lys
965 970 975
Glu Lys Arg Ala Arg Ile Glu Asp Asp Gln Ser Thr Arg Asn Ile Ser
980 985 990
Ser Ser Ser Pro Pro Glu Lys Glu Gln Pro Pro Arg Glu Glu Pro Arg
995 1000 1005
Val Pro Pro Leu Lys Ile Gln Leu Ser Lys Ile Gly Pro Pro Phe Ile
1010 1015 1020
Ile Lys Ser Gln Pro Val Ser Lys Pro Glu Ser Arg Ala Ser Thr Ser
1025 1030 1035 1040
Thr Ser Val Ser Gly Gly Arg Asn Thr Gly Ala Arg Thr Leu Ala Asp
1045 1050 1055
Ile Lys Ala Arg Ala Gln Gln Ala Arg Ala Gln Arg Glu Ala Ala Ala
1060 1065 1070
Ala Ala Ala Val Ala Ala Ala Ala Ser Ile Val Ser Gly Ala Met Gly
1075 1080 1085
Ser Pro Gly Glu Gly Gly Lys Thr Arg Thr Leu Ala His Ile Lys Glu
1090 1095 1100
Gln Thr Lys Ala Lys Leu Phe Ala Lys His Gln Ala Arg Ala His Leu
1105 1110 1115 1120
Phe Gln Thr Ser Lys Glu Thr Arg Leu Pro Pro Pro Leu Ser Ser Lys
1125 1130 1135
Glu Gly Pro Pro Asn Leu Glu Val Ser Ser Thr Pro Glu Thr Lys Met
1140 1145 1150
Glu Gly Ser Thr Gly Val Ile Ile Val Asn Pro Asn Cys Arg Ser Pro
1155 1160 1165
Ser Asn Lys Ser Ala His Leu Arg Glu Thr Thr Thr Val Leu Gln Gln
1170 1175 1180
Ser Leu Asn Pro Ser Lys Leu Pro Glu Thr Ala Thr Asp Leu Ser Val
1185 1190 1195 1200
His Ser Ser Asp Glu Asn Ile Pro Val Ser His Leu Ser Glu Lys Ile
1205 1210 1215
Val Ser Ser Thr Ser Ser Glu Asn Ser Ser Val Pro Met Leu Phe Asn
1220 1225 1230
Lys Asn Ser Val Pro Val Ser Val Cys Ser Thr Ala Ile Ser Gly Ala
1235 1240 1245
Ile Lys Glu His Pro Phe Val Ser Ser Val Asp Lys Ser Ser Val Leu
1250 1255 1260
Met Ser Val Asp Ser Ala Asn Thr Thr Ile Ser Ala Cys Asn Ile Ser
1265 1270 1275 1280
Met Leu Lys Thr Ile Gln Gly Thr Asp Thr Pro Cys Ile Ala Ile Ile
1285 1290 1295
Pro Lys Cys Ile Glu Ser Thr Pro Ile Ser Ala Thr Thr Glu Gly Ser
1300 1305 1310
Ser Ile Ser Ser Ser Met Asp Asp Lys Gln Leu Leu Ile Ser Ser Ser
1315 1320 1325
Ser Ala Ser Asn Leu Val Ser Thr Gln Tyr Thr Ser Val Pro Thr Pro
1330 1335 1340
Ser Ile Gly Asn Asn Leu Pro Asn Leu Ser Thr Ser Ser Val Leu Ile
1345 1350 1355 1360
Pro Pro Met Gly Ile Asn Asn Arg Phe Pro Ser Glu Lys Ile Ala Ile
1365 1370 1375
Pro Gly Ser Glu Glu Gln Ala Thr Val Ser Met Gly Thr Thr Val Arg
1380 1385 1390
Ala Ala Leu Ser Cys Ser Asp Ser Val Ala Val Thr Asp Ser Leu Val
1395 1400 1405
Ala His Pro Thr Val Ala Met Phe Thr Gly Asn Met Leu Thr Ile Asn
1410 1415 1420
Ser Tyr Asp Ser Pro Pro Lys Leu Ser Ala Glu Ser Leu Asp Lys Asn
1425 1430 1435 1440
Ser Gly Pro Arg Asn Arg Ala Asp Asn Ser Gly Lys Pro Gln Gln Pro
1445 1450 1455
Pro Gly Gly Phe Ala Pro Ala Ala Ile Asn Arg Ser Ile Pro Cys Lys
1460 1465 1470
Val Ile Val Asp His Ser Thr Thr Leu Thr Ser Ser Leu Ser Leu Thr
1475 1480 1485
Val Ser Val Glu Ser Ser Glu Ala Ser Leu Asp Leu Gln Gly Arg Pro
1490 1495 1500
Val Arg Thr Glu Ala Ser Val Gln Pro Val Ala Cys Pro Gln Val Ser
1505 1510 1515 1520
Val Ile Ser Arg Pro Glu Pro Val Ala Asn Glu Gly Ile Asp His Ser
1525 1530 1535
Ser Thr Phe Ile Ala Ala Ser Ala Ala Lys Gln Asp Ser Lys Thr Leu
1540 1545 1550
Pro Ala Thr Cys Thr Ser Leu Arg Glu Leu Pro Leu Val Pro Asp Lys
1555 1560 1565
Leu Asn Glu Pro Thr Ala Pro Ser His Asn Phe Ala Glu Gln Ala Arg
1570 1575 1580
Gly Pro Ala Pro Phe Lys Ser Glu Ala Asp Thr Thr Cys Ser Asn Gln
1585 1590 1595 1600
Tyr Asn Pro Ser Asn Arg Ile Cys Trp Asn Asp Asp Gly Met Arg Ser
1605 1610 1615
Thr Gly Gln Pro Leu Val Thr His Ser Gly Ser Ser Lys Gln Lys Glu
1620 1625 1630
Tyr Leu Glu Gln Ser Cys Pro Lys Ala Ile Lys Thr Glu His Ala Asn
1635 1640 1645
Tyr Leu Asn Val Ser Glu Leu His Pro Arg Asn Leu Val Thr Asn Val
1650 1655 1660
Ala Leu Pro Val Lys Ser Glu Leu His Glu Ala Asp Lys Gly Phe Arg
1665 1670 1675 1680
Met Asp Thr Glu Asp Phe Pro Gly Pro Glu Leu Pro Pro Pro Ala Ala
1685 1690 1695
Glu Gly Ala Ser Ser Val Gln Gln Thr Gln Asn Met Lys Ala Ser Thr
1700 1705 1710
Ser Ser Pro Met Glu Glu Ala Ile Ser Leu Ala Thr Asp Ala Leu Lys
1715 1720 1725
Arg Val Pro Gly Ala Gly Ser Ser Gly Cys Arg Leu Ser Ser Val Glu
1730 1735 1740
Ala Asn Asn Pro Leu Val Thr Gln Leu Leu Gln Gly Asn Leu Pro Leu
1745 1750 1755 1760
Glu Lys Val Leu Pro Gln Pro Arg Leu Gly Ala Lys Leu Glu Ile Asn
1765 1770 1775
Arg Leu Pro Leu Pro Leu Gln Thr Thr Ser Val Gly Lys Thr Ala Pro
1780 1785 1790
Glu Arg Asn Val Glu Ile Pro Pro Ser Ser Pro Asn Pro Asp Gly Lys
1795 1800 1805
Gly Tyr Leu Ala Gly Thr Leu Ala Pro Leu Gln Met Arg Lys Arg Glu
1810 1815 1820
Asn His Pro Lys Lys Arg Val Ala Arg Thr Val Gly Glu His Thr Gln
1825 1830 1835 1840
Val Lys Cys Glu Pro Gly Lys Leu Leu Val Glu Pro Asp Val Lys Gly
1845 1850 1855
Val Pro Cys Val Ile Ser Ser Gly Ile Ser Gln Leu Gly His Ser Gln
1860 1865 1870
Pro Phe Lys Gln Glu Trp Leu Asn Lys His Ser Met Gln Asn Arg Ile
1875 1880 1885
Val His Ser Pro Glu Val Lys Gln Gln Lys Arg Leu Leu Pro Ser Cys
1890 1895 1900
Ser Phe Gln Gln Asn Leu Phe His Val Asp Lys Asn Gly Gly Phe His
1905 1910 1915 1920
Thr Asp Ala Gly Thr Ser His Arg Gln Gln Phe Tyr Gln Met Pro Val
1925 1930 1935
Ala Ala Arg Gly Pro Ile Pro Thr Ala Ala Leu Leu Gln Ala Ser Ser
1940 1945 1950
Lys Thr Pro Val Gly Cys Asn Ala Phe Ala Phe Asn Arg His Leu Glu
1955 1960 1965
Gln Lys Gly Leu Gly Glu Val Ser Leu Ser Ser Ala Pro His Gln Leu
1970 1975 1980
Arg Leu Ala Asn Met Leu Ser Pro Asn Met Pro Met Lys Glu Gly Asp
1985 1990 1995 2000
Glu Val Gly Gly Thr Ala His Thr Met Pro Asn Lys Ala Leu Val His
2005 2010 2015
Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Leu Ala Leu Pro
2020 2025 2030
Pro Pro Pro Pro Pro Pro Pro Pro Leu Pro Pro Pro Leu Pro Asn Ala
2035 2040 2045
Glu Val Pro Ser Asp Gln Lys Gln Pro Pro Val Thr Met Glu Thr Thr
2050 2055 2060
Lys Arg Leu Ser Trp Pro Gln Ser Thr Gly Ile Cys Ser Asn Ile Lys
2065 2070 2075 2080
Ser Glu Pro Leu Ser Phe Glu Glu Gly Leu Ser Ser Ser Cys Glu Leu
2085 2090 2095
Gly Met Lys Gln Val Ser Tyr Asp Gln Asn Glu Met Lys Glu Gln Leu
2100 2105 2110
Lys Ala Phe Ala Leu Lys Ser Ala Asp Phe Ser Ser Tyr Leu Leu Ser
2115 2120 2125
Glu Pro Gln Lys Pro Phe Thr Gln Leu Ala Ala Gln Lys Met Gln Val
2130 2135 2140
Gln Gln Gln Gln Gln Leu Cys Gly Asn Tyr Pro Thr Ile His Phe Gly
2145 2150 2155 2160
Ser Thr Ser Phe Lys Arg Ala Ala Ser Ala Ile Glu Lys Ser Ile Gly
2165 2170 2175
Ile Leu Gly Ser Gly Ser Asn Pro Ala Thr Gly Leu Ser Gly Gln Asn
2180 2185 2190
Ala Gln Met Pro Val Gln Asn Phe Ala Asp Ser Ser Asn Ala Asp Glu
2195 2200 2205
Leu Glu Leu Lys Cys Ser Cys Arg Leu Lys Ala Met Ile Val Cys Lys
2210 2215 2220
Gly Cys Gly Ala Phe Cys His Asp Asp Cys Ile Gly Pro Ser Lys Leu
2225 2230 2235 2240
Cys Val Ala Cys Leu Val Val Arg
2245
Claims (10)
1.突变的ASXL3 cDNA,其与野生型ASXL3 cDNA相比至少具有下列复合杂合突变:(c.2168C>G,c.5449C>G);
其中,所述野生型ASXL3基因的cDNA序列如SEQ ID NO:1所示。
2.包含权利要求1所述的突变的ASXL3 cDNA的载体。
3.包含权利要求1所述的突变的ASXL3 cDNA的宿主细胞。
4.包含权利要求1所述的突变的ASXL3 cDNA的非人类动物作为先天性心脏病动物模型的应用。
5.特异性检测权利要求1所述的突变的ASXL3 cDNA的诊断剂在制备用于诊断先天性心脏病的试剂或试剂盒中的应用。
6.根据权利要求5所述的应用,所述试剂包括引物或探针,和/或,所述试剂盒包括引物或探针。
7.根据权利要求5所述的应用,所述试剂用于检测ASXL3蛋白表达水平。
8.野生型ASXL3蛋白在制备用于治疗权利要求1所述的突变的ASXL3 cDNA导致的先天性心脏病的试剂或试剂盒中的应用。
9.基因编辑试剂在制备用于治疗权利要求1所述的突变的ASXL3 cDNA导致的先天性心脏病的试剂或试剂盒中的应用,所述基因编辑试剂包括能够纠正患者中权利要求1所述的突变的ASXL3 cDNA对应的突变ASXL3基因而使所述突变ASXL3基因恢复为野生型ASXL3基因的试剂。
10.突变的ASXL3基因,其与野生型ASXL3基因相比,在cDNA水平上至少具有下列复合杂合突变:(c.2168C>G,c.5449C>G);
其中,所述野生型ASXL3基因的cDNA序列如SEQ ID NO:1所示。
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