CN107475259B

CN107475259B - 汉族人群家族性扩张型心肌病的筛查试剂盒

Info

Publication number: CN107475259B
Application number: CN201710732660.2A
Authority: CN
Inventors: 舒先红; 王小林; 周年伟; 秦胜梅; 仇子龙; 张翼; 潘翠珍; 赵维鹏
Original assignee: Zhongshan Hospital Fudan University
Current assignee: Fuyi Tianwen Shanghai Biotechnology Co ltd
Priority date: 2017-08-24
Filing date: 2017-08-24
Publication date: 2020-08-11
Anticipated expiration: 2037-08-24
Also published as: CN107475259A

Abstract

本发明涉及汉族人群家族性扩张型心肌病的筛查试剂盒。本发明运用二代测序技术，通过外显子捕获富集全基因组DNA编码序列，发现了扩张型心肌病相关的致病基因及致病突变，包括：Chmp4c基因c.488A>G突变、LMNA基因c.961C>T突变和MYH7基因c.2458G>C突变，基于此提供了检测以上突变的扩张型心肌病筛查试剂盒。应用本发明的试剂盒能够提高扩张型心肌病患者早期检出率，有利于早期预防和治疗，提高患者生存率。

Description

汉族人群家族性扩张型心肌病的筛查试剂盒

技术领域

本发明涉及生物医学的疾病诊断技术领域，具体地说，涉及汉族人群家族性扩张型心肌病致病基因及突变位点的发现，和基于该致病基因及突变位点的扩张型心肌病筛查试剂盒。

背景技术

随着二代测序技术(Next-Generation Sequencing，NGS)的出现，特别是与外显子组捕获技术相结合的NGS能快速准确的了解基因序列信息，极大地帮助我们了解遗传性疾病，通过对家族相关基因的比对分析，能够较准确地发现致病基因及突变。

扩张型心肌病(Dilated Cardiomyopathy，DCM)是以左心室或双心室扩大，心室收缩功能障碍、心室壁变薄为主要特点的一种原发性心肌病，是导致心源性猝死和心力衰竭的主要原因。通过在患者家族中进行相关致病基因的研究发现，家族遗传所占的比例较高。家族性DCM的临床表型存在异质性，携带同一致病基因的家系不同成员之间的临床表现不尽相同，这可能与年龄，性别，基因突变的部位、类型等因素有关。根据以往研究报道统计，由于受限于检测技术以及对DCM整体认识水平，家族性DCM相关致病基因及突变检出率不到30％。经典的Sanger测序法准确性高，但检测序列的长度有限，效率较低，仅适用于筛选已知致病基因突变位点，很大程度上阻碍了DCM的致病基因检测。由于不同人种的遗传信息可能有差异，目前遗传分析中使用的数据欧美人群占很大的比例，汉族人群的数据较少，因此需要在汉族人群中近一步筛查研究。

专利文献CN1824776A，公开日2006.08.30，公开了目前已经有8个染色体定位与扩张型心肌病有关，并已确定了7个主要致病基因，包括：肌动蛋白(Actin)、肌营养不良蛋白(Dystrophy)、tafazzin、桥粒蛋白(Desmin)、δ-sarcoglycan、SCN5A和Lamin A/C，该发明还发现LMNA基因中G244A突变或者lamin A蛋白质中E82K突变会导致患者疾病如心脏疾病特别是扩张型心肌病的发生，基于此，提供了诊断患者疾病(如心脏疾病特别是扩张型心肌病)或者确定患者对疾病(如心脏疾病特别是扩张型心肌病)的遗传易感性的方法，所述方法包括检测来自所述患者的样品的LMNA基因中第244位G突变如G244A突变的存在或者lamin A蛋白质中第82位E突变如E82K突变的存在。专利文献CN103509867A，公开日2014.01.15，筛选出中国汉族人群最易感的4个散发性扩张型心肌病致病基因：MYBPC3、SCN5A、MYH7和MYPN，基于此开发出对中国汉族人群散发性扩张型心肌病有效的早期诊断方法和诊断试剂盒，有效提高扩张型心肌病患者早期检出率，从而做到早期治疗，提高患者生存率。

然而，发现新的致病基因及突变位点对于提高扩张型心肌病的筛查准确率来说仍然是十分必要的。

发明内容

本申请发明人运用二代测序技术发现了汉族人群家族性扩张型心肌病新的致病基因及突变位点，基于此完成了本发明。

第一方面，本发明提供一种分离的编码突变体的核酸分子或其片段，所述的核酸分子或其片段选自下列中的任一种：

d)与SEQ ID NO:1相比，具有c.488A>G突变；

e)与SEQ ID NO:7相比，具有c.961 C>T突变；

f)与SEQ ID NO:13相比，具有c.2458 G>C突变。

第二方面，本发明提供了一种分离的多肽或其片段，所述的多肽或其片段选自下列中的任一种：

d)与SEQ ID NO:2相比，具有p.Glu 163 Gly突变；

e)与SEQ ID NO:8相比，具有p.Arg 321 Ter突变；

f)与SEQ ID NO:14相比，具有p.Ala 820 Pro突变。

第三方面，本发明提供了一种用于筛查扩张型心肌病或筛选易患扩张型心肌病生物样品的试剂盒，含有：适于检测Chmp4c基因突变体、LMNA基因突变体或MYH7基因突变体的试剂，其中与SEQ ID NO:1相比，所述的Chmp4c基因突变体具有c.488A>G突变，与SEQ IDNO:7相比，所述的LMNA基因突变体具有c.961 C>T突变，与SEQ ID NO:13相比，所述的MYH7基因突变体具有c.2458G>C突变。

所述的扩张型心肌病为家族性扩张型心肌病。

所述的扩张型心肌病其患病个体属于汉族人群。

第四方面，本发明提供了一种筛查扩张型心肌病或筛选易患扩张型心肌病生物样品的系统，包括：

核酸提取装置，所述的核酸提取装置用于从所述的生物样品提取核酸样本；

核酸序列确定装置，所述的核酸序列确定装置与所述的核酸提取装置相连，用于对所述的核酸样本进行分析，以便确定所述的核酸样本的核酸序列；

判断装置，所述的判断装置与所述的核酸序列确定装置相连，以便基于所述核酸样本的核酸序列与SEQ ID NO:1相比，是否具有c.488A>G突变，或与SEQ ID NO:7相比，是否具有c.961 C>T突变，或与SEQ ID NO:13相比，是否具有c.2458G>C突变，判断所述的生物样品是否属于或易患扩张型心肌病。

作为一个具体例，所述的核酸提取装置进一步包括：RNA提取单元，所述的RNA提取单元用于从所述的生物样品提取RNA样本；以及反转录单元，所述的反转录单元与所述RNA提取单元相连，用于对所述的RNA样本进行反转录反应，以便获得cDNA样本，所述的cDNA样本构成所述的核酸样本。

作为一个具体例，所述的核酸序列确定装置进一步包括：文库构建单元，所述的文库构建单元用于针对所述核酸样本，构建核酸测序文库；以及测序单元，所述的测序单元与所述文库构建单元相连，用于对所述的核酸测序文库进行测序，以便获得由多个测序数据构成的测序结果。

第五方面，本发明提供了正常的Chmp4c基因或者正常的Chmp4c蛋白质在制备药物中的用途，所述的药物用于治疗或者预防扩张型心肌病，所述的患者具有Chmp4c基因c.488A>G突变或Chmp4c蛋白p.Glu 163 Gly突变。

第六方面，本发明提供了正常的LMNA基因或者正常的LMNA蛋白质在制备药物中的用途，所述的药物用于治疗或者预防扩张型心肌病，所述的患者具有LMNA基因c.961 C>T突变或LMNA蛋白p.Arg 321 Ter突变。

第七方面，本发明提供了正常的MYH7基因或者正常的MYH7蛋白质在制备药物中的用途，所述的药物用于治疗或者预防扩张型心肌病，所述的患者具有MYH7基因c.2458 G>C突变或MYH7蛋白p.Ala 820 Pro突变。

本文中，所述的“核酸分子”的类型不受特别限制，可以是任何包含与突变体的编码基因相对应的脱氧核糖核苷酸和/或核糖核苷酸的聚合物，包括但不限于DNA、RNA或cDNA。所述核酸，本领域技术人员应当理解，实际包括互补双链的任意一条，或者两条。为了方便，在本说明书和权利要求书中，虽然多数情况下只给出了一条链，但实际上也公开了与之互补的另一条链。例如，提及SEQ ID NO:1，实际包括其互补序列。本领域技术人员还可以理解，利用一条链可以检测另一条链，反之亦然。

所述的“生物样品”的类型并不受特别限制，只要从该生物样品中能够提取到反映生物样品是否存在突变的核酸样本即可。根据本发明的实施例，生物样品可以为选自人体血液、皮肤、皮下组织的至少一种，优选外周血。由此，可以方便地进行取样和检测，从而能够进一步提高筛选易患DCM的生物样品的效率。根据本发明的实施例，这里所使用的术语“核酸样本”应做广义理解，其可以是任何能够反映生物样品中是否存在突变的样本，例如可以是从生物样品中直接提取的全基因组DNA，也可以是该全基因组中包含致病基因编码序列的一部分，可以是从生物样品中提取的总RNA，也可以是从生物样品中提取的mRNA。

所述的“适于检测基因突变体的试剂”应做广义理解，即可以是检测病基因编码基因的试剂，也可以是检测突变体多肽的试剂，例如可以采用识别特异性位点的抗体。

本发明优点在于：

本发明运用二代测序技术，通过外显子捕获富集全基因组DNA编码序列，发现了扩张型心肌病相关的致病基因及致病突变，包括：Chmp4c基因c.488A>G突变、LMNA基因c.961C>T突变和MYH7基因c.2458 G>C突变，能够提高扩张型心肌病患者早期检出率，有利于早期预防和治疗，提高患者生存率。

附图说明

附图1是家系1的研究资料。

附图2是家系2的研究资料。

附图3是家系3的研究资料。

具体实施方式

下面结合附图对本发明提供的具体实施方式作详细说明。若未特别指明，实施例中所采用的技术手段为本领域技术人员所熟知的常规手段，可以参照《分子克隆实验指南》第3版或者相关产品进行，所采用的试剂和产品也均为可商业获得的。未详细描述的各种过程和方法是本领域中公知的常规方法，所用试剂的来源、商品名以及有必要列出其组成成分者，均在首次出现时标明，其后所用相同试剂如无特殊说明，均以首次标明的内容相同。

实施例1 Chmp4c(c.488A>G，p.Glu 163 Gly)

收集在我院就诊的DCM患者及其家系成员(家系1，图1)的临床资料，采集相关家系成员外周血并抽提DNA，对该家系成员行全基因组外显子测序，寻找致病基因，用Sanger测序对家系其他成员等进行验证。

1.一般临床资料收集：收集该家系所有成员详细的临床资料，包括体格检查，发病年龄，初发症状，血清肌酸激酶，纽约心功能分级，常规心电图，超声心动图，根据需要行动态心电图检查。所有研究对象签署知情同意书后，采集其外周血标本，按照试剂盒说明书步骤提取基因组DNA。本研究得到复旦大学附属中山医院伦理委员会的批准(2016-16B)，所有研究对象都知情同意并签署知情同意书。

2.全外显子组测序：对家系成员的外周血DNA进行全外显子测序实验：样品核酸提取，超声打断，TruSeq DNA Sample Preparation试剂盒处理两端连接测序接头构建成文库，使用Roche Nimblegen SeqCap EZ v5.1试剂盒捕获全外显子区域，采用illumina XTEN平台进行高通量测序，数据质量Q30比例大于90％，外显子目标区域测序深度中位值>50×，95％目标区域测序深度>30×，外显子丢失率<0.2％。

3.测序数据分析：基因组测序原始数据经比对分析(bwamem/disco vardenovo/freebayes)取SNV及SV数据；CNV数据使用EulerCNV及CNVnator综合判断；SNV数据经inhouse cohort、dbSNP138及1000G_OMNI2.5注释携带率，使用snpEff及in house深度神经网络分析流程注释功能；剪切位点预测使用in house C++/R深度神经网络模型；CNV/SV数据经in house cohort、1000G及公开CNV数据库数据过滤携带率，使用Langya注释；信号转导通路分析使用in house R/Python/Perl package；OMIM/Monarch/ExAC数据库分析使用inhouse Perl/R API；表型基因型相关神经网络分析使用Langya/Marshes。数据解读参考美国医学遗传学和基因组学学院(American College of Medical Genetics and Genomics,ACMG)相关指南；变异命名参照HGVS建议的规则给出(http://www.hgvs.org/mutnomen/)。

结果：

由图1可知，该家系目前共有33个成员，DCM患者7名。其中，本家系先证者为一51岁女性患者(Ⅲ4)，反复胸闷、晕厥来我院就诊。入院检查心电图提示房颤，三度房室传导阻滞，左束支传导阻滞；超声心动图提示全心增大伴左心室收缩功能减弱，左心室射血分数LVEF＝34％，诊断为扩张型心肌病，接受了相关药物治疗并植入了起搏器。先证者的表哥(III7，III10)均诊断为扩张型心肌病，接受了相关药物治疗并植入了起搏器。先证者的表姐(III6)因扩张型心肌病去世。

收集上述DCM患者家系中患者及家系内正常人的外周血样本，经全外显子组测序和数据分析发现，先证者(Ⅲ4)和先证者表哥(III7，III10)的Chmp4c基因均存在c.488A>G，p.Glu 163 Gly的突变，成员(IV3，V3)为突变携带者，可能由于年龄原因暂时未表现出明显的扩张型心肌病临床症状，其他所有家系成员均不存在该突变。

野生型Chmp4c基因的CDS序列如SEQ ID NO:1所示，其编码的蛋白质的氨基酸序列如SEQ ID NO:2所示。Chmp4c基因突变体的CDS序列如SEQ ID NO:3所示，其编码的蛋白质的氨基酸序列如SEQ ID NO:4所示。

4.Sanger法测序验证：对该家系中患者及正常人，以及200名家系外正常人的Chmp4c基因进行检测：针对Chmp4c基因的c.488A>G突变设计引物，然后通过PCR扩增、产物纯化和测序的方法获得Chmp4c基因序列，确定序列测定结果属于突变型还是野生型，验证Chmp4c基因的c.488A>G突变与DCM之间的相关性。

突变引物序列为：

F：cgcccaagaaatctcagaag(SEQ ID NO:5)；

R：ctgtgctgggagagaagagg(SEQ ID NO:6)。

结果表明，该家系中患者均携带Chmp4c基因的c.488A>G突变，而家系中正常人和200名家系外正常人均不携带该突变。

综上所述，证明Chmp4c基因的c.488A>G突变为DCM的致病突变。

实施例2 LMNA(c.961 C>T，p.Arg321Ter)

收集在我院就诊的DCM患者及其家系成员(家系2，图2)的临床资料，采集相关家系成员外周血并抽提DNA，对该家系成员行全基因组外显子测序，寻找致病基因，用Sanger测序对家系其他成员等进行验证。

结果：

由图1可知，该家系目前共有49个成员，DCM患者8名。其中，本家系先证者为一安徽籍43岁男性患者(Ⅲ7)，反复心悸、晕厥来我院就诊，初步诊断为心律失常，房室传导阻滞。入院检查心电图提示房颤，三度房室传导阻滞，左束支传导阻滞；超声心动图提示左心房左心室增大伴左心室收缩功能减退，左心室射血分数LVEF＝42％。该患者胸片提示心脏扩大；血肌酸激酶和肌钙蛋白T较正常值稍偏高，既往无高血压、冠心病及糖尿病病史，该患者诊断为扩张型心肌病，接受了相关药物治疗并植入了起搏器。先证者的表哥(III5)，46岁，2年前被诊断为房颤，DCM，也接受了起搏器植入术。

收集上述DCM患者家系中患者及家系内正常人的外周血样本，经全外显子组测序和数据分析发现，先证者(Ⅲ7)和先证者表哥(III5)的LMNA基因均存在c.961 C>T，p.Arg321Ter的突变，成员(IV6，IV10)为突变携带者，可能由于年龄原因暂时未表现出明显的扩张型心肌病临床症状，其他所有家系成员均不存在该突变。

野生型LMNA基因的CDS序列如SEQ ID NO:7所示，其编码的蛋白质的氨基酸序列如SEQ ID NO:8所示。LMNA基因突变体的CDS序列如SEQ ID NO:9所示，其编码的蛋白质的氨基酸序列如SEQ ID NO:10所示。

4.Sanger法测序验证：对该家系中患者及正常人，以及200名家系外正常人的LMNA基因进行检测：针对LMNA基因的c.961 C>T突变设计引物，然后通过PCR扩增、产物纯化和测序的方法获得LMNA基因序列，确定序列测定结果属于突变型还是野生型，验证LMNA基因的c.961 C>T突变与DCM之间的相关性。

突变引物序列为：

F：cctctctgcccagctcag(SEQ ID NO:11)；

R：gccagcttgatgtccagaag(SEQ ID NO:12)。

结果表明，该家系中患者均携带LMNA基因的c.961 C>T突变，而家系中正常人和200名家系外正常人均不携带该突变。

综上所述，证明LMNA基因的c.961 C>T突变为DCM的致病突变。

实施例3 MYH7(c.2458G>C，p.Ala820Pro)

收集在我院就诊的DCM患者及其家系成员(家系3，图3)的临床资料，采集相关家系成员外周血并抽提DNA，对该家系成员行全基因组外显子测序，寻找致病基因，用Sanger测序对家系其他成员等进行验证。

结果：

由图1可知，该家系目前共有8个成员，DCM患者3名。其中，本家系先证者为一42岁男性患者(II3)，反复胸闷、胸痛来我院就诊。入院检查心电图提示房室传导阻滞；超声心动图提示左心增大伴左心室收缩功能减弱，左心室射血分数LVEF＝41％，诊断为扩张型心肌病，接受了相关药物治疗并植入了起搏器。先证者的哥哥(II2)也为扩张型心肌病，接受相关药物治疗。先证者的父亲(I2)因心肌病去世。

收集上述DCM患者家系中患者及家系内正常人的外周血样本，经全外显子组测序和数据分析发现，先证者(II3)和先证者哥哥(II3)的MYH7基因均存在c.2458G>C，p.Ala820Pro的突变，其他所有家系成员均不存在该突变。

野生型MYH7基因的CDS序列如SEQ ID NO:13所示，其编码的蛋白质的氨基酸序列如SEQ ID NO:14所示。MYH7基因突变体的CDS序列如SEQ ID NO:15所示，其编码的蛋白质的氨基酸序列如SEQ ID NO:16所示。

4.Sanger法测序验证：对该家系中患者及正常人，以及200名家系外正常人的MYH7基因进行检测：针对MYH7基因的c.2458G>C突变设计引物，然后通过PCR扩增、产物纯化和测序的方法获得MYH7基因序列，确定序列测定结果属于突变型还是野生型，验证MYH7基因的c.2458G>C突变与DCM之间的相关性。

突变引物序列为：

F：gactccctgctggtaatcca(SEQ ID NO:17)；

R：cctctttgaggcgtgtgaac(SEQ ID NO:18)。

结果表明，该家系中患者均携带MYH7基因的c.2458G>C突变，而家系中正常人和200名家系外正常人均不携带该突变。

综上所述，证明MYH7基因的c.2458G>C突变为DCM的致病突变。

实施例4筛查扩张型心肌病/易患扩张型心肌病生物样品的试剂盒

一种筛查扩张型心肌病/易患扩张型心肌病生物样品的试剂盒，其至少包含能够检测以下任一种突变的引物：Chmp4c基因的c.488A>G突变、LMNA基因的c.961 C>T突变、MYH7基因的c.2458 G>C突变，用于筛查易患扩张型心肌病的生物样品。优选地，用于检测Chmp4c基因的c.488A>G突变的引物系列如SEQ ID NO:5和SEQ ID NO:6所示，用于检测LMNA基因的c.961C>T突变的引物系列如SEQ ID NO:11和SEQ ID NO:12所示，用于检测MYH7基因的c.2458 G>C突变的引物系列如SEQ ID NO:17和SEQ ID NO:18所示。

利用上述试剂盒筛选患有或易患DCM的生物样品的具体步骤为：提取待测者DNA，以所提取的DNA为模板与上述引物进行PCR反应，并按照本领域常规方法对PCR产物纯化，将纯化的产物进行测序，然后通过观察测序所得到的序列是否具有对应突变，能够有效地检测本发明的Chmp4c、LMNA、MYH7基因突变体在待测者DNA中是否存在，从而能够有效地检测待测者是否易患DCM，进一步，能够从待测者中筛选出易患DCM的生物样品。

以上所述仅是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员，在不脱离本发明方法的前提下，还可以做出若干改进和补充，这些改进和补充也应视为本发明的保护范围。

SEQUENCE LISTING

<110> 复旦大学附属中山医院

<120> 汉族人群家族性扩张型心肌病的筛查试剂盒

<130> /

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<170> PatentIn version 3.3

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cgcttggcgg tctacatcga ccgtgtgcgc tcgctggaaa cggagaacgc agggctgcgc 180

cttcgcatca ccgagtctga agaggtggtc agccgcgagg tgtccggcat caaggccgcc 240

tacgaggccg agctcgggga tgcccgcaag acccttgact cagtagccaa ggagcgcgcc 300

cgcctgcagc tggagctgag caaagtgcgt gaggagttta aggagctgaa agcgcgcaat 360

accaagaagg agggtgacct gatagctgct caggctcggc tgaaggacct ggaggctctg 420

ctgaactcca aggaggccgc actgagcact gctctcagtg agaagcgcac gctggagggc 480

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aagcaacttc aggatgagat gctgcggcgg gtggatgctg agaacaggct gcagaccatg 600

aaggaggaac tggacttcca gaagaacatc tacagtgagg agctgcgtga gaccaagcgc 660

cgtcatgaga cccgactggt ggagattgac aatgggaagc agcgtgagtt tgagagccgg 720

ctggcggatg cgctgcagga actgcgggcc cagcatgagg accaggtgga gcagtataag 780

aaggagctgg agaagactta ttctgccaag ctggacaatg ccaggcagtc tgctgagagg 840

aacagcaacc tggtgggggc tgcccacgag gagctgcagc agtcgcgcat ccgcatcgac 900

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ggagctgggg ccacccacag cccccctacc gacctggtgt ggaaggcaca gaacacctgg 1560

ggctgcggga acagcctgcg tacggctctc atcaactcca ctggggaaga agtggccatg 1620

cgcaagctgg tgcgctcagt gactgtggtt gaggacgacg aggatgagga tggagatgac 1680

ctgctccatc accaccacgg ctcccactgc agcagctcgg gggaccccgc tgagtacaac 1740

ctgcgctcgc gcaccgtgct gtgcgggacc tgcgggcagc ctgccgacaa ggcatctgcc 1800

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acggtcactc gcagctaccg cagtgtgggg ggcagtgggg gtggcagctt cggggacaat 1920

ctggtcaccc gctcctacct cctgggcaac tccagccccc gaacccagag cccccagaac 1980

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Gln Pro Ala Asp Lys Ala Ser Ala Ser Gly Ser Gly Ala Gln Val Gly

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Gly Pro Ile Ser Ser Gly Ser Ser Ala Ser Ser Val Thr Val Thr Arg

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Ser Tyr Arg Ser Val Gly Gly Ser Gly Gly Gly Ser Phe Gly Asp Asn

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Leu Val Thr Arg Ser Tyr Leu Leu Gly Asn Ser Ser Pro Arg Thr Gln

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Ser Pro Gln Asn Cys Ser Ile Met

660

<210> 9

<211> 1995

<212> DNA

<213> human

<400> 9

atggagaccc cgtcccagcg gcgcgccacc cgcagcgggg cgcaggccag ctccactccg 60

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cgcttggcgg tctacatcga ccgtgtgcgc tcgctggaaa cggagaacgc agggctgcgc 180

cttcgcatca ccgagtctga agaggtggtc agccgcgagg tgtccggcat caaggccgcc 240

tacgaggccg agctcgggga tgcccgcaag acccttgact cagtagccaa ggagcgcgcc 300

cgcctgcagc tggagctgag caaagtgcgt gaggagttta aggagctgaa agcgcgcaat 360

accaagaagg agggtgacct gatagctgct caggctcggc tgaaggacct ggaggctctg 420

ctgaactcca aggaggccgc actgagcact gctctcagtg agaagcgcac gctggagggc 480

gagctgcatg atctgcgggg ccaggtggcc aagcttgagg cagccctagg tgaggccaag 540

aagcaacttc aggatgagat gctgcggcgg gtggatgctg agaacaggct gcagaccatg 600

aaggaggaac tggacttcca gaagaacatc tacagtgagg agctgcgtga gaccaagcgc 660

cgtcatgaga cccgactggt ggagattgac aatgggaagc agcgtgagtt tgagagccgg 720

ctggcggatg cgctgcagga actgcgggcc cagcatgagg accaggtgga gcagtataag 780

aaggagctgg agaagactta ttctgccaag ctggacaatg ccaggcagtc tgctgagagg 840

aacagcaacc tggtgggggc tgcccacgag gagctgcagc agtcgcgcat ccgcatcgac 900

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ggctgcggga acagcctgcg tacggctctc atcaactcca ctggggaaga agtggccatg 1620

cgcaagctgg tgcgctcagt gactgtggtt gaggacgacg aggatgagga tggagatgac 1680

ctgctccatc accaccacgg ctcccactgc agcagctcgg gggaccccgc tgagtacaac 1740

ctgcgctcgc gcaccgtgct gtgcgggacc tgcgggcagc ctgccgacaa ggcatctgcc 1800

agcggctcag gagcccaggt gggcggaccc atctcctctg gctcttctgc ctccagtgtc 1860

acggtcactc gcagctaccg cagtgtgggg ggcagtgggg gtggcagctt cggggacaat 1920

ctggtcaccc gctcctacct cctgggcaac tccagccccc gaacccagag cccccagaac 1980

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<210> 10

<211> 320

<212> PRT

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Met Glu Thr Pro Ser Gln Arg Arg Ala Thr Arg Ser Gly Ala Gln Ala

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Ser Ser Thr Pro Leu Ser Pro Thr Arg Ile Thr Arg Leu Gln Glu Lys

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<210> 11

<211> 18

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<213> 人工序列

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cctctctgcc cagctcag 18

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<212> DNA

<213> 人工序列

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<210> 13

<211> 5808

<212> DNA

<213> human

<400> 13

atgggagatt cggagatggc agtctttggg gctgccgccc cctacctgcg caagtcagag 60

aaggagcggc tagaagcgca gaccaggcct tttgacctca agaaggatgt cttcgtgcct 120

gatgacaaac aggagtttgt caaggccaag atcgtgtctc gagagggtgg caaagtcact 180

gccgagaccg agtatggcaa gacagtgacc gtgaaggagg accaggtgat gcagcagaac 240

ccacccaagt tcgacaaaat cgaggacatg gccatgctga ccttcctgca tgagcccgcg 300

gtgctctaca acctcaagga tcgctacggc tcctggatga tctacaccta ctcgggcctc 360

ttctgtgtca ccgtcaaccc ttacaagtgg ctgccggtgt acactcctga ggtggtggct 420

gcctaccggg gcaagaagag gagcgaggcc ccgccccaca tcttctccat ctccgacaac 480

gcctatcagt acatgctgac agacagagaa aaccagtcca tcctgatcac cggagaatcc 540

ggagcaggga agacagtcaa caccaagagg gtcatccagt actttgctgt tattgcagcc 600

attggggacc gcagcaagaa ggaccagagc ccgggcaagg gcaccctgga ggaccagatc 660

atccaggcca accctgctct ggaggccttt ggcaatgcca agaccgtccg gaacgacaac 720

tcctcccgct tcgggaaatt cattcgaatt cattttgggg caacaggaaa gttggcatct 780

gcagacatag agacctatct tctggaaaaa tccagagtta ttttccagct gaaagcagag 840

agagattatc acattttcta ccaaatcctg tctaacaaaa agcctgagct gctggacatg 900

ctgctgatca ccaacaaccc ctacgattat gcattcatct cccaaggaga gaccaccgtg 960

gcctccattg atgacgctga ggagctcatg gccactgata acgcttttga tgtgctgggc 1020

ttcacttcag aggagaaaaa ctccatgtat aagctgacag gcgccatcat gcactttgga 1080

aacatgaagt tcaagctgaa gcagcgggag gagcaggcgg agccagacgg cactgaagag 1140

gctgacaagt ctgcctacct catggggctg aactcagccg acctgctcaa ggggctgtgc 1200

caccctcggg tgaaagtggg caatgagtac gtcaccaagg ggcagaatgt ccagcaggtg 1260

atatatgcca ctggggcact ggccaaggca gtgtatgaga ggatgttcaa ctggatggtg 1320

acgcgcatca atgccaccct ggagaccaag cagccacgcc agtacttcat aggagtcctg 1380

gacatcgctg gcttcgagat cttcgatttc aacagctttg agcagctctg catcaacttc 1440

accaacgaga agctgcagca gttcttcaac caccacatgt ttgtgctgga gcaggaggag 1500

tacaagaagg agggcatcga gtggacattc attgactttg gcatggacct gcaggcctgc 1560

attgacctca tcgagaagcc catgggcatc atgtccatcc tggaagagga gtgcatgttc 1620

cccaaggcca ccgacatgac cttcaaggcc aagctgtttg acaaccacct gggcaaatcc 1680

gccaacttcc agaagccacg caatatcaag gggaagcctg aagcccactt ctccctgatc 1740

cactatgccg gcatcgtgga ctacaacatc attggctggc tgcagaagaa caaggatcct 1800

ctcaatgaga ctgtcgtggg cttgtatcag aagtcttccc tcaagctgct cagcaccctg 1860

tttgccaact atgctggggc tgatgcgcct attgagaagg gcaaaggcaa ggccaagaaa 1920

ggctcgtcct ttcagactgt gtcagctctg cacagggaaa atctgaacaa gctgatgacc 1980

aacttgcgct ccacccatcc ccactttgta cgttgtatca tccctaatga gacaaagtct 2040

ccaggggtga tggacaaccc cctggtcatg caccagctgc gctgcaatgg tgtgctggag 2100

ggcatccgca tctgcaggaa aggcttcccc aaccgcatcc tctacgggga cttccggcag 2160

aggtatcgca tcctgaaccc agcggccatc cctgagggac agttcattga tagcaggaag 2220

ggggcagaga agctgctcag ctccctggac attgatcaca accagtacaa gtttggccac 2280

accaaggtgt tcttcaaggc cgggctgctg gggctgctgg aggaaatgag ggacgagagg 2340

ctgagccgca tcatcacgcg tatccaggcc cagtcccgag gtgtgctcgc cagaatggag 2400

tacaaaaagc tgctggaacg tagagactcc ctgctggtaa tccagtggaa cattcgggcc 2460

ttcatggggg tcaagaattg gccctggatg aagctctact tcaagatcaa gccgctgctg 2520

aagagtgcag aaagagagaa ggagatggcc tccatgaagg aggagttcac acgcctcaaa 2580

gaggcgctag agaagtccga ggctcgccgc aaggagctgg aggagaagat ggtgtccctg 2640

ctgcaggaga agaatgacct gcagctccaa gtgcaggcgg aacaagacaa cctggcagat 2700

gctgaggagc gctgtgatca gctgatcaaa aacaagattc agctggaggc caaggtgaag 2760

gagatgaacg agaggctgga ggatgaggag gagatgaatg ctgagctcac tgccaagaag 2820

cgcaagctgg aagatgagtg ctcagagctc aaaagggaca tcgatgatct ggagctgaca 2880

ctggccaaag tggagaagga gaaacacgca acagagaaca aggtgaaaaa cctgacagag 2940

gagatggctg ggctggatga gatcattgcc aagctgacca aggagaagaa agctctgcaa 3000

gaggcccacc aacaggctct ggatgacctt caggccgagg aggacaaggt caacaccctg 3060

actaaggcca aagtcaagct ggagcagcaa gtggatgatc tggaaggatc cctggagcaa 3120

gagaagaagg tgcgcatgga cctggagcga gcgaagcgga agctggaggg cgacctgaag 3180

ctgacccagg agagcatcat ggacctggag aatgacaagc agcagctgga tgagcggctg 3240

aaaaaaaaag actttgagct gaatgctctc aacgcaagga ttgaggatga acaggccctc 3300

ggcagccagc tgcagaagaa gctcaaggag cttcaggcac gcatcgagga gctggaggag 3360

gagctggagg ccgagcgcac cgccagggct aaggtggaga agctgcgctc agacctgtct 3420

cgggagctgg aggagatcag cgagcggctg gaagaggccg gcggggccac gtccgtgcag 3480

atcgagatga acaagaagcg cgaggccgag ttccagaaga tgcggcggga cctggaggag 3540

gccacgctgc agcacgaggc cactgccgcg gccctgcgca agaagcacgc cgacagcgtg 3600

gccgagctgg gcgagcagat cgacaacctg cagcgggtga agcagaagct ggagaaggag 3660

aagagcgagt tcaagctgga gctggatgac gtcacctcca acatggagca gatcatcaag 3720

gccaaggcta acctggagaa gatgtgccgg accttggaag accagatgaa tgagcaccgg 3780

agcaaggcgg aggagaccca gcgttctgtc aacgacctca ccagccagcg ggccaagttg 3840

caaaccgaga atggtgagct gtcccggcag ctggatgaga aggaggcact gatctcccag 3900

ctgacccgag gcaagctcac ctacacccag cagctggagg acctcaagag gcagctggag 3960

gaggaggtta aggcgaagaa cgccctggcc cacgcactgc agtcggcccg gcatgactgc 4020

gacctgctgc gggagcagta cgaggaggag acggaggcca aggccgagct gcagcgcgtc 4080

ctttccaagg ccaactcgga ggtggcccag tggaggacca agtatgagac ggacgccatt 4140

cagcggactg aggagctcga ggaggccaag aagaagctgg cccagcggct gcaggaagct 4200

gaggaggccg tggaggctgt taatgccaag tgctcctcgc tggagaagac caagcaccgg 4260

ctacagaatg agatcgagga cttgatggtg gacgtagagc gctccaatgc tgctgctgca 4320

gccctggaca agaagcagag gaacttcgac aagatcctgg ccgagtggaa gcagaagtat 4380

gaggagtcgc agtcggagct ggagtcctcg cagaaggagg ctcgctccct cagcacagag 4440

ctcttcaaac tcaagaacgc ctatgaggag tccctggaac atctggagac cttcaagcgg 4500

gagaacaaaa acctgcagga ggagatctcc gacttgactg agcagttggg ttccagcgga 4560

aagactatcc atgagctgga gaaggtccga aagcagctgg aggccgagaa gatggagctg 4620

cagtcagccc tggaggaggc cgaggcctcc ctggagcacg aggagggcaa gatcctccgg 4680

gcccagctgg agttcaacca gatcaaggca gagatcgagc ggaagctggc agagaaggac 4740

gaggagatgg aacaggccaa gcgcaaccac ctgcgggtgg tggactcgct gcagacctcc 4800

ctggacgcag agacacgcag ccgcaacgag gccctgaggg tgaagaagaa gatggaagga 4860

gacctcaatg agatggagat ccagctcagc cacgccaacc gcatggccgc cgaggcccag 4920

aagcaagtca agagcctcca gagcttgttg aaggacaccc agattcagct ggacgatgca 4980

gtccgtgcca acgacgacct gaaggagaac atcgccatcg tggagcggcg caacaacctg 5040

ctgcaggctg agctggagga gttgcgtgcc gtggtggagc agacagagcg gtcccggaag 5100

ctggcggagc aggagctgat tgagactagt gagcgggtgc agctgctgca ttcccagaac 5160

accagcctca tcaaccagaa gaagaagatg gatgctgacc tgtcccagct ccagactgaa 5220

gtggaggagg cagtgcagga gtgcaggaat gctgaggaga aggccaagaa ggccatcacg 5280

gatgccgcca tgatggcaga ggagctgaag aaggagcagg acaccagcgc ccacctggag 5340

cgcatgaaga agaacatgga acagaccatt aaggacctgc agcaccggct ggacgaagcc 5400

gagcagatcg ccctcaaggg cggcaagaag cagctgcaga agctggaagc gcgggtgcgg 5460

gagctggaga atgagctgga ggccgagcag aagcgcaacg cagagtcggt gaagggcatg 5520

aggaagagcg agcggcgcat caaggagctc acctaccaga cggaggagga caggaaaaac 5580

ctgctgcggc tgcaggacct ggtagacaag ctgcagctaa aggtcaaggc ctacaagcgc 5640

caggccgagg aggcggagga gcaagccaac accaacctgt ccaagttccg caaggtgcag 5700

cacgagctgg atgaggcaga ggagcgggcg gacatcgccg agtcccaggt caacaagctg 5760

cgggccaaga gccgtgacat tggcacgaag ggcttgaatg aggagtag 5808

<210> 14

<211> 1935

<212> PRT

<213> human

<400> 14

Met Gly Asp Ser Glu Met Ala Val Phe Gly Ala Ala Ala Pro Tyr Leu

1 5 10 15

Arg Lys Ser Glu Lys Glu Arg Leu Glu Ala Gln Thr Arg Pro Phe Asp

20 25 30

Leu Lys Lys Asp Val Phe Val Pro Asp Asp Lys Gln Glu Phe Val Lys

35 40 45

Ala Lys Ile Val Ser Arg Glu Gly Gly Lys Val Thr Ala Glu Thr Glu

50 55 60

Tyr Gly Lys Thr Val Thr Val Lys Glu Asp Gln Val Met Gln Gln Asn

65 70 75 80

Pro Pro Lys Phe Asp Lys Ile Glu Asp Met Ala Met Leu Thr Phe Leu

85 90 95

His Glu Pro Ala Val Leu Tyr Asn Leu Lys Asp Arg Tyr Gly Ser Trp

100 105 110

Met Ile Tyr Thr Tyr Ser Gly Leu Phe Cys Val Thr Val Asn Pro Tyr

115 120 125

Lys Trp Leu Pro Val Tyr Thr Pro Glu Val Val Ala Ala Tyr Arg Gly

130 135 140

Lys Lys Arg Ser Glu Ala Pro Pro His Ile Phe Ser Ile Ser Asp Asn

145 150 155 160

Ala Tyr Gln Tyr Met Leu Thr Asp Arg Glu Asn Gln Ser Ile Leu Ile

165 170 175

Thr Gly Glu Ser Gly Ala Gly Lys Thr Val Asn Thr Lys Arg Val Ile

180 185 190

Gln Tyr Phe Ala Val Ile Ala Ala Ile Gly Asp Arg Ser Lys Lys Asp

195 200 205

Gln Ser Pro Gly Lys Gly Thr Leu Glu Asp Gln Ile Ile Gln Ala Asn

210 215 220

Pro Ala Leu Glu Ala Phe Gly Asn Ala Lys Thr Val Arg Asn Asp Asn

225 230 235 240

Ser Ser Arg Phe Gly Lys Phe Ile Arg Ile His Phe Gly Ala Thr Gly

245 250 255

Lys Leu Ala Ser Ala Asp Ile Glu Thr Tyr Leu Leu Glu Lys Ser Arg

260 265 270

Val Ile Phe Gln Leu Lys Ala Glu Arg Asp Tyr His Ile Phe Tyr Gln

275 280 285

Ile Leu Ser Asn Lys Lys Pro Glu Leu Leu Asp Met Leu Leu Ile Thr

290 295 300

Asn Asn Pro Tyr Asp Tyr Ala Phe Ile Ser Gln Gly Glu Thr Thr Val

305 310 315 320

Ala Ser Ile Asp Asp Ala Glu Glu Leu Met Ala Thr Asp Asn Ala Phe

325 330 335

Asp Val Leu Gly Phe Thr Ser Glu Glu Lys Asn Ser Met Tyr Lys Leu

340 345 350

Thr Gly Ala Ile Met His Phe Gly Asn Met Lys Phe Lys Leu Lys Gln

355 360 365

Arg Glu Glu Gln Ala Glu Pro Asp Gly Thr Glu Glu Ala Asp Lys Ser

370 375 380

Ala Tyr Leu Met Gly Leu Asn Ser Ala Asp Leu Leu Lys Gly Leu Cys

385 390 395 400

His Pro Arg Val Lys Val Gly Asn Glu Tyr Val Thr Lys Gly Gln Asn

405 410 415

Val Gln Gln Val Ile Tyr Ala Thr Gly Ala Leu Ala Lys Ala Val Tyr

420 425 430

Glu Arg Met Phe Asn Trp Met Val Thr Arg Ile Asn Ala Thr Leu Glu

435 440 445

Thr Lys Gln Pro Arg Gln Tyr Phe Ile Gly Val Leu Asp Ile Ala Gly

450 455 460

Phe Glu Ile Phe Asp Phe Asn Ser Phe Glu Gln Leu Cys Ile Asn Phe

465 470 475 480

Thr Asn Glu Lys Leu Gln Gln Phe Phe Asn His His Met Phe Val Leu

485 490 495

Glu Gln Glu Glu Tyr Lys Lys Glu Gly Ile Glu Trp Thr Phe Ile Asp

500 505 510

Phe Gly Met Asp Leu Gln Ala Cys Ile Asp Leu Ile Glu Lys Pro Met

515 520 525

Gly Ile Met Ser Ile Leu Glu Glu Glu Cys Met Phe Pro Lys Ala Thr

530 535 540

Asp Met Thr Phe Lys Ala Lys Leu Phe Asp Asn His Leu Gly Lys Ser

545 550 555 560

Ala Asn Phe Gln Lys Pro Arg Asn Ile Lys Gly Lys Pro Glu Ala His

565 570 575

Phe Ser Leu Ile His Tyr Ala Gly Ile Val Asp Tyr Asn Ile Ile Gly

580 585 590

Trp Leu Gln Lys Asn Lys Asp Pro Leu Asn Glu Thr Val Val Gly Leu

595 600 605

Tyr Gln Lys Ser Ser Leu Lys Leu Leu Ser Thr Leu Phe Ala Asn Tyr

610 615 620

Ala Gly Ala Asp Ala Pro Ile Glu Lys Gly Lys Gly Lys Ala Lys Lys

625 630 635 640

Gly Ser Ser Phe Gln Thr Val Ser Ala Leu His Arg Glu Asn Leu Asn

645 650 655

Lys Leu Met Thr Asn Leu Arg Ser Thr His Pro His Phe Val Arg Cys

660 665 670

Ile Ile Pro Asn Glu Thr Lys Ser Pro Gly Val Met Asp Asn Pro Leu

675 680 685

Val Met His Gln Leu Arg Cys Asn Gly Val Leu Glu Gly Ile Arg Ile

690 695 700

Cys Arg Lys Gly Phe Pro Asn Arg Ile Leu Tyr Gly Asp Phe Arg Gln

705 710 715 720

Arg Tyr Arg Ile Leu Asn Pro Ala Ala Ile Pro Glu Gly Gln Phe Ile

725 730 735

Asp Ser Arg Lys Gly Ala Glu Lys Leu Leu Ser Ser Leu Asp Ile Asp

740 745 750

His Asn Gln Tyr Lys Phe Gly His Thr Lys Val Phe Phe Lys Ala Gly

755 760 765

Leu Leu Gly Leu Leu Glu Glu Met Arg Asp Glu Arg Leu Ser Arg Ile

770 775 780

Ile Thr Arg Ile Gln Ala Gln Ser Arg Gly Val Leu Ala Arg Met Glu

785 790 795 800

Tyr Lys Lys Leu Leu Glu Arg Arg Asp Ser Leu Leu Val Ile Gln Trp

805 810 815

Asn Ile Arg Ala Phe Met Gly Val Lys Asn Trp Pro Trp Met Lys Leu

820 825 830

Tyr Phe Lys Ile Lys Pro Leu Leu Lys Ser Ala Glu Arg Glu Lys Glu

835 840 845

Met Ala Ser Met Lys Glu Glu Phe Thr Arg Leu Lys Glu Ala Leu Glu

850 855 860

Lys Ser Glu Ala Arg Arg Lys Glu Leu Glu Glu Lys Met Val Ser Leu

865 870 875 880

Leu Gln Glu Lys Asn Asp Leu Gln Leu Gln Val Gln Ala Glu Gln Asp

885 890 895

Asn Leu Ala Asp Ala Glu Glu Arg Cys Asp Gln Leu Ile Lys Asn Lys

900 905 910

Ile Gln Leu Glu Ala Lys Val Lys Glu Met Asn Glu Arg Leu Glu Asp

915 920 925

Glu Glu Glu Met Asn Ala Glu Leu Thr Ala Lys Lys Arg Lys Leu Glu

930 935 940

Asp Glu Cys Ser Glu Leu Lys Arg Asp Ile Asp Asp Leu Glu Leu Thr

945 950 955 960

Leu Ala Lys Val Glu Lys Glu Lys His Ala Thr Glu Asn Lys Val Lys

965 970 975

Asn Leu Thr Glu Glu Met Ala Gly Leu Asp Glu Ile Ile Ala Lys Leu

980 985 990

Thr Lys Glu Lys Lys Ala Leu Gln Glu Ala His Gln Gln Ala Leu Asp

995 1000 1005

Asp Leu Gln Ala Glu Glu Asp Lys Val Asn Thr Leu Thr Lys Ala

1010 1015 1020

Lys Val Lys Leu Glu Gln Gln Val Asp Asp Leu Glu Gly Ser Leu

1025 1030 1035

Glu Gln Glu Lys Lys Val Arg Met Asp Leu Glu Arg Ala Lys Arg

1040 1045 1050

Lys Leu Glu Gly Asp Leu Lys Leu Thr Gln Glu Ser Ile Met Asp

1055 1060 1065

Leu Glu Asn Asp Lys Gln Gln Leu Asp Glu Arg Leu Lys Lys Lys

1070 1075 1080

Asp Phe Glu Leu Asn Ala Leu Asn Ala Arg Ile Glu Asp Glu Gln

1085 1090 1095

Ala Leu Gly Ser Gln Leu Gln Lys Lys Leu Lys Glu Leu Gln Ala

1100 1105 1110

Arg Ile Glu Glu Leu Glu Glu Glu Leu Glu Ala Glu Arg Thr Ala

1115 1120 1125

Arg Ala Lys Val Glu Lys Leu Arg Ser Asp Leu Ser Arg Glu Leu

1130 1135 1140

Glu Glu Ile Ser Glu Arg Leu Glu Glu Ala Gly Gly Ala Thr Ser

1145 1150 1155

Val Gln Ile Glu Met Asn Lys Lys Arg Glu Ala Glu Phe Gln Lys

1160 1165 1170

Met Arg Arg Asp Leu Glu Glu Ala Thr Leu Gln His Glu Ala Thr

1175 1180 1185

Ala Ala Ala Leu Arg Lys Lys His Ala Asp Ser Val Ala Glu Leu

1190 1195 1200

Gly Glu Gln Ile Asp Asn Leu Gln Arg Val Lys Gln Lys Leu Glu

1205 1210 1215

Lys Glu Lys Ser Glu Phe Lys Leu Glu Leu Asp Asp Val Thr Ser

1220 1225 1230

Asn Met Glu Gln Ile Ile Lys Ala Lys Ala Asn Leu Glu Lys Met

1235 1240 1245

Cys Arg Thr Leu Glu Asp Gln Met Asn Glu His Arg Ser Lys Ala

1250 1255 1260

Glu Glu Thr Gln Arg Ser Val Asn Asp Leu Thr Ser Gln Arg Ala

1265 1270 1275

Lys Leu Gln Thr Glu Asn Gly Glu Leu Ser Arg Gln Leu Asp Glu

1280 1285 1290

Lys Glu Ala Leu Ile Ser Gln Leu Thr Arg Gly Lys Leu Thr Tyr

1295 1300 1305

Thr Gln Gln Leu Glu Asp Leu Lys Arg Gln Leu Glu Glu Glu Val

1310 1315 1320

Lys Ala Lys Asn Ala Leu Ala His Ala Leu Gln Ser Ala Arg His

1325 1330 1335

Asp Cys Asp Leu Leu Arg Glu Gln Tyr Glu Glu Glu Thr Glu Ala

1340 1345 1350

Lys Ala Glu Leu Gln Arg Val Leu Ser Lys Ala Asn Ser Glu Val

1355 1360 1365

Ala Gln Trp Arg Thr Lys Tyr Glu Thr Asp Ala Ile Gln Arg Thr

1370 1375 1380

Glu Glu Leu Glu Glu Ala Lys Lys Lys Leu Ala Gln Arg Leu Gln

1385 1390 1395

Glu Ala Glu Glu Ala Val Glu Ala Val Asn Ala Lys Cys Ser Ser

1400 1405 1410

Leu Glu Lys Thr Lys His Arg Leu Gln Asn Glu Ile Glu Asp Leu

1415 1420 1425

Met Val Asp Val Glu Arg Ser Asn Ala Ala Ala Ala Ala Leu Asp

1430 1435 1440

Lys Lys Gln Arg Asn Phe Asp Lys Ile Leu Ala Glu Trp Lys Gln

1445 1450 1455

Lys Tyr Glu Glu Ser Gln Ser Glu Leu Glu Ser Ser Gln Lys Glu

1460 1465 1470

Ala Arg Ser Leu Ser Thr Glu Leu Phe Lys Leu Lys Asn Ala Tyr

1475 1480 1485

Glu Glu Ser Leu Glu His Leu Glu Thr Phe Lys Arg Glu Asn Lys

1490 1495 1500

Asn Leu Gln Glu Glu Ile Ser Asp Leu Thr Glu Gln Leu Gly Ser

1505 1510 1515

Ser Gly Lys Thr Ile His Glu Leu Glu Lys Val Arg Lys Gln Leu

1520 1525 1530

Glu Ala Glu Lys Met Glu Leu Gln Ser Ala Leu Glu Glu Ala Glu

1535 1540 1545

Ala Ser Leu Glu His Glu Glu Gly Lys Ile Leu Arg Ala Gln Leu

1550 1555 1560

Glu Phe Asn Gln Ile Lys Ala Glu Ile Glu Arg Lys Leu Ala Glu

1565 1570 1575

Lys Asp Glu Glu Met Glu Gln Ala Lys Arg Asn His Leu Arg Val

1580 1585 1590

Val Asp Ser Leu Gln Thr Ser Leu Asp Ala Glu Thr Arg Ser Arg

1595 1600 1605

Asn Glu Ala Leu Arg Val Lys Lys Lys Met Glu Gly Asp Leu Asn

1610 1615 1620

Glu Met Glu Ile Gln Leu Ser His Ala Asn Arg Met Ala Ala Glu

1625 1630 1635

Ala Gln Lys Gln Val Lys Ser Leu Gln Ser Leu Leu Lys Asp Thr

1640 1645 1650

Gln Ile Gln Leu Asp Asp Ala Val Arg Ala Asn Asp Asp Leu Lys

1655 1660 1665

Glu Asn Ile Ala Ile Val Glu Arg Arg Asn Asn Leu Leu Gln Ala

1670 1675 1680

Glu Leu Glu Glu Leu Arg Ala Val Val Glu Gln Thr Glu Arg Ser

1685 1690 1695

Arg Lys Leu Ala Glu Gln Glu Leu Ile Glu Thr Ser Glu Arg Val

1700 1705 1710

Gln Leu Leu His Ser Gln Asn Thr Ser Leu Ile Asn Gln Lys Lys

1715 1720 1725

Lys Met Asp Ala Asp Leu Ser Gln Leu Gln Thr Glu Val Glu Glu

1730 1735 1740

Ala Val Gln Glu Cys Arg Asn Ala Glu Glu Lys Ala Lys Lys Ala

1745 1750 1755

Ile Thr Asp Ala Ala Met Met Ala Glu Glu Leu Lys Lys Glu Gln

1760 1765 1770

Asp Thr Ser Ala His Leu Glu Arg Met Lys Lys Asn Met Glu Gln

1775 1780 1785

Thr Ile Lys Asp Leu Gln His Arg Leu Asp Glu Ala Glu Gln Ile

1790 1795 1800

Ala Leu Lys Gly Gly Lys Lys Gln Leu Gln Lys Leu Glu Ala Arg

1805 1810 1815

Val Arg Glu Leu Glu Asn Glu Leu Glu Ala Glu Gln Lys Arg Asn

1820 1825 1830

Ala Glu Ser Val Lys Gly Met Arg Lys Ser Glu Arg Arg Ile Lys

1835 1840 1845

Glu Leu Thr Tyr Gln Thr Glu Glu Asp Arg Lys Asn Leu Leu Arg

1850 1855 1860

Leu Gln Asp Leu Val Asp Lys Leu Gln Leu Lys Val Lys Ala Tyr

1865 1870 1875

Lys Arg Gln Ala Glu Glu Ala Glu Glu Gln Ala Asn Thr Asn Leu

1880 1885 1890

Ser Lys Phe Arg Lys Val Gln His Glu Leu Asp Glu Ala Glu Glu

1895 1900 1905

Arg Ala Asp Ile Ala Glu Ser Gln Val Asn Lys Leu Arg Ala Lys

1910 1915 1920

Ser Arg Asp Ile Gly Thr Lys Gly Leu Asn Glu Glu

1925 1930 1935

<210> 15

<211> 5808

<212> DNA

<213> human

<400> 15

atgggagatt cggagatggc agtctttggg gctgccgccc cctacctgcg caagtcagag 60

aaggagcggc tagaagcgca gaccaggcct tttgacctca agaaggatgt cttcgtgcct 120

gatgacaaac aggagtttgt caaggccaag atcgtgtctc gagagggtgg caaagtcact 180

gccgagaccg agtatggcaa gacagtgacc gtgaaggagg accaggtgat gcagcagaac 240

ccacccaagt tcgacaaaat cgaggacatg gccatgctga ccttcctgca tgagcccgcg 300

gtgctctaca acctcaagga tcgctacggc tcctggatga tctacaccta ctcgggcctc 360

ttctgtgtca ccgtcaaccc ttacaagtgg ctgccggtgt acactcctga ggtggtggct 420

gcctaccggg gcaagaagag gagcgaggcc ccgccccaca tcttctccat ctccgacaac 480

gcctatcagt acatgctgac agacagagaa aaccagtcca tcctgatcac cggagaatcc 540

ggagcaggga agacagtcaa caccaagagg gtcatccagt actttgctgt tattgcagcc 600

attggggacc gcagcaagaa ggaccagagc ccgggcaagg gcaccctgga ggaccagatc 660

atccaggcca accctgctct ggaggccttt ggcaatgcca agaccgtccg gaacgacaac 720

tcctcccgct tcgggaaatt cattcgaatt cattttgggg caacaggaaa gttggcatct 780

gcagacatag agacctatct tctggaaaaa tccagagtta ttttccagct gaaagcagag 840

agagattatc acattttcta ccaaatcctg tctaacaaaa agcctgagct gctggacatg 900

ctgctgatca ccaacaaccc ctacgattat gcattcatct cccaaggaga gaccaccgtg 960

gcctccattg atgacgctga ggagctcatg gccactgata acgcttttga tgtgctgggc 1020

ttcacttcag aggagaaaaa ctccatgtat aagctgacag gcgccatcat gcactttgga 1080

aacatgaagt tcaagctgaa gcagcgggag gagcaggcgg agccagacgg cactgaagag 1140

gctgacaagt ctgcctacct catggggctg aactcagccg acctgctcaa ggggctgtgc 1200

caccctcggg tgaaagtggg caatgagtac gtcaccaagg ggcagaatgt ccagcaggtg 1260

atatatgcca ctggggcact ggccaaggca gtgtatgaga ggatgttcaa ctggatggtg 1320

acgcgcatca atgccaccct ggagaccaag cagccacgcc agtacttcat aggagtcctg 1380

gacatcgctg gcttcgagat cttcgatttc aacagctttg agcagctctg catcaacttc 1440

accaacgaga agctgcagca gttcttcaac caccacatgt ttgtgctgga gcaggaggag 1500

tacaagaagg agggcatcga gtggacattc attgactttg gcatggacct gcaggcctgc 1560

attgacctca tcgagaagcc catgggcatc atgtccatcc tggaagagga gtgcatgttc 1620

cccaaggcca ccgacatgac cttcaaggcc aagctgtttg acaaccacct gggcaaatcc 1680

gccaacttcc agaagccacg caatatcaag gggaagcctg aagcccactt ctccctgatc 1740

cactatgccg gcatcgtgga ctacaacatc attggctggc tgcagaagaa caaggatcct 1800

ctcaatgaga ctgtcgtggg cttgtatcag aagtcttccc tcaagctgct cagcaccctg 1860

tttgccaact atgctggggc tgatgcgcct attgagaagg gcaaaggcaa ggccaagaaa 1920

ggctcgtcct ttcagactgt gtcagctctg cacagggaaa atctgaacaa gctgatgacc 1980

aacttgcgct ccacccatcc ccactttgta cgttgtatca tccctaatga gacaaagtct 2040

ccaggggtga tggacaaccc cctggtcatg caccagctgc gctgcaatgg tgtgctggag 2100

ggcatccgca tctgcaggaa aggcttcccc aaccgcatcc tctacgggga cttccggcag 2160

aggtatcgca tcctgaaccc agcggccatc cctgagggac agttcattga tagcaggaag 2220

ggggcagaga agctgctcag ctccctggac attgatcaca accagtacaa gtttggccac 2280

accaaggtgt tcttcaaggc cgggctgctg gggctgctgg aggaaatgag ggacgagagg 2340

ctgagccgca tcatcacgcg tatccaggcc cagtcccgag gtgtgctcgc cagaatggag 2400

tacaaaaagc tgctggaacg tagagactcc ctgctggtaa tccagtggaa cattcggccc 2460

ttcatggggg tcaagaattg gccctggatg aagctctact tcaagatcaa gccgctgctg 2520

aagagtgcag aaagagagaa ggagatggcc tccatgaagg aggagttcac acgcctcaaa 2580

gaggcgctag agaagtccga ggctcgccgc aaggagctgg aggagaagat ggtgtccctg 2640

ctgcaggaga agaatgacct gcagctccaa gtgcaggcgg aacaagacaa cctggcagat 2700

gctgaggagc gctgtgatca gctgatcaaa aacaagattc agctggaggc caaggtgaag 2760

gagatgaacg agaggctgga ggatgaggag gagatgaatg ctgagctcac tgccaagaag 2820

cgcaagctgg aagatgagtg ctcagagctc aaaagggaca tcgatgatct ggagctgaca 2880

ctggccaaag tggagaagga gaaacacgca acagagaaca aggtgaaaaa cctgacagag 2940

gagatggctg ggctggatga gatcattgcc aagctgacca aggagaagaa agctctgcaa 3000

gaggcccacc aacaggctct ggatgacctt caggccgagg aggacaaggt caacaccctg 3060

actaaggcca aagtcaagct ggagcagcaa gtggatgatc tggaaggatc cctggagcaa 3120

gagaagaagg tgcgcatgga cctggagcga gcgaagcgga agctggaggg cgacctgaag 3180

ctgacccagg agagcatcat ggacctggag aatgacaagc agcagctgga tgagcggctg 3240

aaaaaaaaag actttgagct gaatgctctc aacgcaagga ttgaggatga acaggccctc 3300

ggcagccagc tgcagaagaa gctcaaggag cttcaggcac gcatcgagga gctggaggag 3360

gagctggagg ccgagcgcac cgccagggct aaggtggaga agctgcgctc agacctgtct 3420

cgggagctgg aggagatcag cgagcggctg gaagaggccg gcggggccac gtccgtgcag 3480

atcgagatga acaagaagcg cgaggccgag ttccagaaga tgcggcggga cctggaggag 3540

gccacgctgc agcacgaggc cactgccgcg gccctgcgca agaagcacgc cgacagcgtg 3600

gccgagctgg gcgagcagat cgacaacctg cagcgggtga agcagaagct ggagaaggag 3660

aagagcgagt tcaagctgga gctggatgac gtcacctcca acatggagca gatcatcaag 3720

gccaaggcta acctggagaa gatgtgccgg accttggaag accagatgaa tgagcaccgg 3780

agcaaggcgg aggagaccca gcgttctgtc aacgacctca ccagccagcg ggccaagttg 3840

caaaccgaga atggtgagct gtcccggcag ctggatgaga aggaggcact gatctcccag 3900

ctgacccgag gcaagctcac ctacacccag cagctggagg acctcaagag gcagctggag 3960

gaggaggtta aggcgaagaa cgccctggcc cacgcactgc agtcggcccg gcatgactgc 4020

gacctgctgc gggagcagta cgaggaggag acggaggcca aggccgagct gcagcgcgtc 4080

ctttccaagg ccaactcgga ggtggcccag tggaggacca agtatgagac ggacgccatt 4140

cagcggactg aggagctcga ggaggccaag aagaagctgg cccagcggct gcaggaagct 4200

gaggaggccg tggaggctgt taatgccaag tgctcctcgc tggagaagac caagcaccgg 4260

ctacagaatg agatcgagga cttgatggtg gacgtagagc gctccaatgc tgctgctgca 4320

gccctggaca agaagcagag gaacttcgac aagatcctgg ccgagtggaa gcagaagtat 4380

gaggagtcgc agtcggagct ggagtcctcg cagaaggagg ctcgctccct cagcacagag 4440

ctcttcaaac tcaagaacgc ctatgaggag tccctggaac atctggagac cttcaagcgg 4500

gagaacaaaa acctgcagga ggagatctcc gacttgactg agcagttggg ttccagcgga 4560

aagactatcc atgagctgga gaaggtccga aagcagctgg aggccgagaa gatggagctg 4620

cagtcagccc tggaggaggc cgaggcctcc ctggagcacg aggagggcaa gatcctccgg 4680

gcccagctgg agttcaacca gatcaaggca gagatcgagc ggaagctggc agagaaggac 4740

gaggagatgg aacaggccaa gcgcaaccac ctgcgggtgg tggactcgct gcagacctcc 4800

ctggacgcag agacacgcag ccgcaacgag gccctgaggg tgaagaagaa gatggaagga 4860

gacctcaatg agatggagat ccagctcagc cacgccaacc gcatggccgc cgaggcccag 4920

aagcaagtca agagcctcca gagcttgttg aaggacaccc agattcagct ggacgatgca 4980

gtccgtgcca acgacgacct gaaggagaac atcgccatcg tggagcggcg caacaacctg 5040

ctgcaggctg agctggagga gttgcgtgcc gtggtggagc agacagagcg gtcccggaag 5100

ctggcggagc aggagctgat tgagactagt gagcgggtgc agctgctgca ttcccagaac 5160

accagcctca tcaaccagaa gaagaagatg gatgctgacc tgtcccagct ccagactgaa 5220

gtggaggagg cagtgcagga gtgcaggaat gctgaggaga aggccaagaa ggccatcacg 5280

gatgccgcca tgatggcaga ggagctgaag aaggagcagg acaccagcgc ccacctggag 5340

cgcatgaaga agaacatgga acagaccatt aaggacctgc agcaccggct ggacgaagcc 5400

gagcagatcg ccctcaaggg cggcaagaag cagctgcaga agctggaagc gcgggtgcgg 5460

gagctggaga atgagctgga ggccgagcag aagcgcaacg cagagtcggt gaagggcatg 5520

aggaagagcg agcggcgcat caaggagctc acctaccaga cggaggagga caggaaaaac 5580

ctgctgcggc tgcaggacct ggtagacaag ctgcagctaa aggtcaaggc ctacaagcgc 5640

caggccgagg aggcggagga gcaagccaac accaacctgt ccaagttccg caaggtgcag 5700

cacgagctgg atgaggcaga ggagcgggcg gacatcgccg agtcccaggt caacaagctg 5760

cgggccaaga gccgtgacat tggcacgaag ggcttgaatg aggagtag 5808

<210> 16

<211> 1935

<212> PRT

<213> human

<400> 16

Met Gly Asp Ser Glu Met Ala Val Phe Gly Ala Ala Ala Pro Tyr Leu

1 5 10 15

Arg Lys Ser Glu Lys Glu Arg Leu Glu Ala Gln Thr Arg Pro Phe Asp

20 25 30

Leu Lys Lys Asp Val Phe Val Pro Asp Asp Lys Gln Glu Phe Val Lys

35 40 45

Ala Lys Ile Val Ser Arg Glu Gly Gly Lys Val Thr Ala Glu Thr Glu

50 55 60

Tyr Gly Lys Thr Val Thr Val Lys Glu Asp Gln Val Met Gln Gln Asn

65 70 75 80

Pro Pro Lys Phe Asp Lys Ile Glu Asp Met Ala Met Leu Thr Phe Leu

85 90 95

His Glu Pro Ala Val Leu Tyr Asn Leu Lys Asp Arg Tyr Gly Ser Trp

100 105 110

Met Ile Tyr Thr Tyr Ser Gly Leu Phe Cys Val Thr Val Asn Pro Tyr

115 120 125

Lys Trp Leu Pro Val Tyr Thr Pro Glu Val Val Ala Ala Tyr Arg Gly

130 135 140

Lys Lys Arg Ser Glu Ala Pro Pro His Ile Phe Ser Ile Ser Asp Asn

145 150 155 160

Ala Tyr Gln Tyr Met Leu Thr Asp Arg Glu Asn Gln Ser Ile Leu Ile

165 170 175

Thr Gly Glu Ser Gly Ala Gly Lys Thr Val Asn Thr Lys Arg Val Ile

180 185 190

Gln Tyr Phe Ala Val Ile Ala Ala Ile Gly Asp Arg Ser Lys Lys Asp

195 200 205

Gln Ser Pro Gly Lys Gly Thr Leu Glu Asp Gln Ile Ile Gln Ala Asn

210 215 220

Pro Ala Leu Glu Ala Phe Gly Asn Ala Lys Thr Val Arg Asn Asp Asn

225 230 235 240

Ser Ser Arg Phe Gly Lys Phe Ile Arg Ile His Phe Gly Ala Thr Gly

245 250 255

Lys Leu Ala Ser Ala Asp Ile Glu Thr Tyr Leu Leu Glu Lys Ser Arg

260 265 270

Val Ile Phe Gln Leu Lys Ala Glu Arg Asp Tyr His Ile Phe Tyr Gln

275 280 285

Ile Leu Ser Asn Lys Lys Pro Glu Leu Leu Asp Met Leu Leu Ile Thr

290 295 300

Asn Asn Pro Tyr Asp Tyr Ala Phe Ile Ser Gln Gly Glu Thr Thr Val

305 310 315 320

Ala Ser Ile Asp Asp Ala Glu Glu Leu Met Ala Thr Asp Asn Ala Phe

325 330 335

Asp Val Leu Gly Phe Thr Ser Glu Glu Lys Asn Ser Met Tyr Lys Leu

340 345 350

Thr Gly Ala Ile Met His Phe Gly Asn Met Lys Phe Lys Leu Lys Gln

355 360 365

Arg Glu Glu Gln Ala Glu Pro Asp Gly Thr Glu Glu Ala Asp Lys Ser

370 375 380

Ala Tyr Leu Met Gly Leu Asn Ser Ala Asp Leu Leu Lys Gly Leu Cys

385 390 395 400

His Pro Arg Val Lys Val Gly Asn Glu Tyr Val Thr Lys Gly Gln Asn

405 410 415

Val Gln Gln Val Ile Tyr Ala Thr Gly Ala Leu Ala Lys Ala Val Tyr

420 425 430

Glu Arg Met Phe Asn Trp Met Val Thr Arg Ile Asn Ala Thr Leu Glu

435 440 445

Thr Lys Gln Pro Arg Gln Tyr Phe Ile Gly Val Leu Asp Ile Ala Gly

450 455 460

Phe Glu Ile Phe Asp Phe Asn Ser Phe Glu Gln Leu Cys Ile Asn Phe

465 470 475 480

Thr Asn Glu Lys Leu Gln Gln Phe Phe Asn His His Met Phe Val Leu

485 490 495

Glu Gln Glu Glu Tyr Lys Lys Glu Gly Ile Glu Trp Thr Phe Ile Asp

500 505 510

Phe Gly Met Asp Leu Gln Ala Cys Ile Asp Leu Ile Glu Lys Pro Met

515 520 525

Gly Ile Met Ser Ile Leu Glu Glu Glu Cys Met Phe Pro Lys Ala Thr

530 535 540

Asp Met Thr Phe Lys Ala Lys Leu Phe Asp Asn His Leu Gly Lys Ser

545 550 555 560

Ala Asn Phe Gln Lys Pro Arg Asn Ile Lys Gly Lys Pro Glu Ala His

565 570 575

Phe Ser Leu Ile His Tyr Ala Gly Ile Val Asp Tyr Asn Ile Ile Gly

580 585 590

Trp Leu Gln Lys Asn Lys Asp Pro Leu Asn Glu Thr Val Val Gly Leu

595 600 605

Tyr Gln Lys Ser Ser Leu Lys Leu Leu Ser Thr Leu Phe Ala Asn Tyr

610 615 620

Ala Gly Ala Asp Ala Pro Ile Glu Lys Gly Lys Gly Lys Ala Lys Lys

625 630 635 640

Gly Ser Ser Phe Gln Thr Val Ser Ala Leu His Arg Glu Asn Leu Asn

645 650 655

Lys Leu Met Thr Asn Leu Arg Ser Thr His Pro His Phe Val Arg Cys

660 665 670

Ile Ile Pro Asn Glu Thr Lys Ser Pro Gly Val Met Asp Asn Pro Leu

675 680 685

Val Met His Gln Leu Arg Cys Asn Gly Val Leu Glu Gly Ile Arg Ile

690 695 700

Cys Arg Lys Gly Phe Pro Asn Arg Ile Leu Tyr Gly Asp Phe Arg Gln

705 710 715 720

Arg Tyr Arg Ile Leu Asn Pro Ala Ala Ile Pro Glu Gly Gln Phe Ile

725 730 735

Asp Ser Arg Lys Gly Ala Glu Lys Leu Leu Ser Ser Leu Asp Ile Asp

740 745 750

His Asn Gln Tyr Lys Phe Gly His Thr Lys Val Phe Phe Lys Ala Gly

755 760 765

Leu Leu Gly Leu Leu Glu Glu Met Arg Asp Glu Arg Leu Ser Arg Ile

770 775 780

Ile Thr Arg Ile Gln Ala Gln Ser Arg Gly Val Leu Ala Arg Met Glu

785 790 795 800

Tyr Lys Lys Leu Leu Glu Arg Arg Asp Ser Leu Leu Val Ile Gln Trp

805 810 815

Asn Ile Arg Pro Phe Met Gly Val Lys Asn Trp Pro Trp Met Lys Leu

820 825 830

Tyr Phe Lys Ile Lys Pro Leu Leu Lys Ser Ala Glu Arg Glu Lys Glu

835 840 845

Met Ala Ser Met Lys Glu Glu Phe Thr Arg Leu Lys Glu Ala Leu Glu

850 855 860

Lys Ser Glu Ala Arg Arg Lys Glu Leu Glu Glu Lys Met Val Ser Leu

865 870 875 880

Leu Gln Glu Lys Asn Asp Leu Gln Leu Gln Val Gln Ala Glu Gln Asp

885 890 895

Asn Leu Ala Asp Ala Glu Glu Arg Cys Asp Gln Leu Ile Lys Asn Lys

900 905 910

Ile Gln Leu Glu Ala Lys Val Lys Glu Met Asn Glu Arg Leu Glu Asp

915 920 925

Glu Glu Glu Met Asn Ala Glu Leu Thr Ala Lys Lys Arg Lys Leu Glu

930 935 940

Asp Glu Cys Ser Glu Leu Lys Arg Asp Ile Asp Asp Leu Glu Leu Thr

945 950 955 960

Leu Ala Lys Val Glu Lys Glu Lys His Ala Thr Glu Asn Lys Val Lys

965 970 975

Asn Leu Thr Glu Glu Met Ala Gly Leu Asp Glu Ile Ile Ala Lys Leu

980 985 990

Thr Lys Glu Lys Lys Ala Leu Gln Glu Ala His Gln Gln Ala Leu Asp

995 1000 1005

Asp Leu Gln Ala Glu Glu Asp Lys Val Asn Thr Leu Thr Lys Ala

1010 1015 1020

Lys Val Lys Leu Glu Gln Gln Val Asp Asp Leu Glu Gly Ser Leu

1025 1030 1035

Glu Gln Glu Lys Lys Val Arg Met Asp Leu Glu Arg Ala Lys Arg

1040 1045 1050

Lys Leu Glu Gly Asp Leu Lys Leu Thr Gln Glu Ser Ile Met Asp

1055 1060 1065

Leu Glu Asn Asp Lys Gln Gln Leu Asp Glu Arg Leu Lys Lys Lys

1070 1075 1080

Asp Phe Glu Leu Asn Ala Leu Asn Ala Arg Ile Glu Asp Glu Gln

1085 1090 1095

Ala Leu Gly Ser Gln Leu Gln Lys Lys Leu Lys Glu Leu Gln Ala

1100 1105 1110

Arg Ile Glu Glu Leu Glu Glu Glu Leu Glu Ala Glu Arg Thr Ala

1115 1120 1125

Arg Ala Lys Val Glu Lys Leu Arg Ser Asp Leu Ser Arg Glu Leu

1130 1135 1140

Glu Glu Ile Ser Glu Arg Leu Glu Glu Ala Gly Gly Ala Thr Ser

1145 1150 1155

Val Gln Ile Glu Met Asn Lys Lys Arg Glu Ala Glu Phe Gln Lys

1160 1165 1170

Met Arg Arg Asp Leu Glu Glu Ala Thr Leu Gln His Glu Ala Thr

1175 1180 1185

Ala Ala Ala Leu Arg Lys Lys His Ala Asp Ser Val Ala Glu Leu

1190 1195 1200

Gly Glu Gln Ile Asp Asn Leu Gln Arg Val Lys Gln Lys Leu Glu

1205 1210 1215

Lys Glu Lys Ser Glu Phe Lys Leu Glu Leu Asp Asp Val Thr Ser

1220 1225 1230

Asn Met Glu Gln Ile Ile Lys Ala Lys Ala Asn Leu Glu Lys Met

1235 1240 1245

Cys Arg Thr Leu Glu Asp Gln Met Asn Glu His Arg Ser Lys Ala

1250 1255 1260

Glu Glu Thr Gln Arg Ser Val Asn Asp Leu Thr Ser Gln Arg Ala

1265 1270 1275

Lys Leu Gln Thr Glu Asn Gly Glu Leu Ser Arg Gln Leu Asp Glu

1280 1285 1290

Lys Glu Ala Leu Ile Ser Gln Leu Thr Arg Gly Lys Leu Thr Tyr

1295 1300 1305

Thr Gln Gln Leu Glu Asp Leu Lys Arg Gln Leu Glu Glu Glu Val

1310 1315 1320

Lys Ala Lys Asn Ala Leu Ala His Ala Leu Gln Ser Ala Arg His

1325 1330 1335

Asp Cys Asp Leu Leu Arg Glu Gln Tyr Glu Glu Glu Thr Glu Ala

1340 1345 1350

Lys Ala Glu Leu Gln Arg Val Leu Ser Lys Ala Asn Ser Glu Val

1355 1360 1365

Ala Gln Trp Arg Thr Lys Tyr Glu Thr Asp Ala Ile Gln Arg Thr

1370 1375 1380

Glu Glu Leu Glu Glu Ala Lys Lys Lys Leu Ala Gln Arg Leu Gln

1385 1390 1395

Glu Ala Glu Glu Ala Val Glu Ala Val Asn Ala Lys Cys Ser Ser

1400 1405 1410

Leu Glu Lys Thr Lys His Arg Leu Gln Asn Glu Ile Glu Asp Leu

1415 1420 1425

Met Val Asp Val Glu Arg Ser Asn Ala Ala Ala Ala Ala Leu Asp

1430 1435 1440

Lys Lys Gln Arg Asn Phe Asp Lys Ile Leu Ala Glu Trp Lys Gln

1445 1450 1455

Lys Tyr Glu Glu Ser Gln Ser Glu Leu Glu Ser Ser Gln Lys Glu

1460 1465 1470

Ala Arg Ser Leu Ser Thr Glu Leu Phe Lys Leu Lys Asn Ala Tyr

1475 1480 1485

Glu Glu Ser Leu Glu His Leu Glu Thr Phe Lys Arg Glu Asn Lys

1490 1495 1500

Asn Leu Gln Glu Glu Ile Ser Asp Leu Thr Glu Gln Leu Gly Ser

1505 1510 1515

Ser Gly Lys Thr Ile His Glu Leu Glu Lys Val Arg Lys Gln Leu

1520 1525 1530

Glu Ala Glu Lys Met Glu Leu Gln Ser Ala Leu Glu Glu Ala Glu

1535 1540 1545

Ala Ser Leu Glu His Glu Glu Gly Lys Ile Leu Arg Ala Gln Leu

1550 1555 1560

Glu Phe Asn Gln Ile Lys Ala Glu Ile Glu Arg Lys Leu Ala Glu

1565 1570 1575

Lys Asp Glu Glu Met Glu Gln Ala Lys Arg Asn His Leu Arg Val

1580 1585 1590

Val Asp Ser Leu Gln Thr Ser Leu Asp Ala Glu Thr Arg Ser Arg

1595 1600 1605

Asn Glu Ala Leu Arg Val Lys Lys Lys Met Glu Gly Asp Leu Asn

1610 1615 1620

Glu Met Glu Ile Gln Leu Ser His Ala Asn Arg Met Ala Ala Glu

1625 1630 1635

Ala Gln Lys Gln Val Lys Ser Leu Gln Ser Leu Leu Lys Asp Thr

1640 1645 1650

Gln Ile Gln Leu Asp Asp Ala Val Arg Ala Asn Asp Asp Leu Lys

1655 1660 1665

Glu Asn Ile Ala Ile Val Glu Arg Arg Asn Asn Leu Leu Gln Ala

1670 1675 1680

Glu Leu Glu Glu Leu Arg Ala Val Val Glu Gln Thr Glu Arg Ser

1685 1690 1695

Arg Lys Leu Ala Glu Gln Glu Leu Ile Glu Thr Ser Glu Arg Val

1700 1705 1710

Gln Leu Leu His Ser Gln Asn Thr Ser Leu Ile Asn Gln Lys Lys

1715 1720 1725

Lys Met Asp Ala Asp Leu Ser Gln Leu Gln Thr Glu Val Glu Glu

1730 1735 1740

Ala Val Gln Glu Cys Arg Asn Ala Glu Glu Lys Ala Lys Lys Ala

1745 1750 1755

Ile Thr Asp Ala Ala Met Met Ala Glu Glu Leu Lys Lys Glu Gln

1760 1765 1770

Asp Thr Ser Ala His Leu Glu Arg Met Lys Lys Asn Met Glu Gln

1775 1780 1785

Thr Ile Lys Asp Leu Gln His Arg Leu Asp Glu Ala Glu Gln Ile

1790 1795 1800

Ala Leu Lys Gly Gly Lys Lys Gln Leu Gln Lys Leu Glu Ala Arg

1805 1810 1815

Val Arg Glu Leu Glu Asn Glu Leu Glu Ala Glu Gln Lys Arg Asn

1820 1825 1830

Ala Glu Ser Val Lys Gly Met Arg Lys Ser Glu Arg Arg Ile Lys

1835 1840 1845

Glu Leu Thr Tyr Gln Thr Glu Glu Asp Arg Lys Asn Leu Leu Arg

1850 1855 1860

Leu Gln Asp Leu Val Asp Lys Leu Gln Leu Lys Val Lys Ala Tyr

1865 1870 1875

Lys Arg Gln Ala Glu Glu Ala Glu Glu Gln Ala Asn Thr Asn Leu

1880 1885 1890

Ser Lys Phe Arg Lys Val Gln His Glu Leu Asp Glu Ala Glu Glu

1895 1900 1905

Arg Ala Asp Ile Ala Glu Ser Gln Val Asn Lys Leu Arg Ala Lys

1910 1915 1920

Ser Arg Asp Ile Gly Thr Lys Gly Leu Asn Glu Glu

1925 1930 1935

<210> 17

<211> 20

<212> DNA

<213> 人工序列

<400> 17

gactccctgc tggtaatcca 20

<210> 18

<211> 20

<212> DNA

<213> 人工序列

<400> 18

gactccctgc tggtaatcca 20

Claims

1.一种分离的编码突变体的核酸分子，其特征在于，所述的核酸分子与SEQ ID NO:1相比，具有c.488 A>G突变。

2.一种分离的多肽，其特征在于，所述的多肽与SEQ ID NO:2相比，具有p.Glu 163 Gly突变。

3.一种试剂在制备筛查扩张型心肌病或筛选易患扩张型心肌病生物样品的试剂盒的应用，其特征在于，所述试剂检测Chmp4c基因与SEQ ID NO:1相比是否存在c.488 A>G突变的试剂。

4.根据权利要求3所述的应用，其特征在于，所述的扩张型心肌病为家族性扩张型心肌病。

5.根据权利要求3或4所述的应用，其特征在于，所述的扩张型心肌病其患病个体属于汉族人群。