CN114317708B - 突变的ttn基因及肥厚型心肌病检测试剂盒 - Google Patents

Abstract

本发明涉及人类遗传学和内科心血管技术领域，具体涉及了一种突变的TTN基因，在基因组位置chr2:179610658处，碱基T突变为碱基G；参考基因组版本是GRCh37。本发明还涉及一种肥厚型心肌病检测试剂盒，包括用于扩增突变的TTN基因的引物。本发明提供的突变的TTN基因可以作为临床辅助诊断的生物标志物；检测该变异的携带者，为受试者提供优生优育指导和遗传咨询，减少患儿出生，对肥厚型心肌病的早期诊断，或者辅助临床判断具有重要意义。

Description

突变的TTN基因及肥厚型心肌病检测试剂盒

技术领域

本发明涉及人类遗传学和内科心血管技术领域，尤其涉及突变的TTN基因及肥厚型心肌病检测试剂盒。

背景技术

肥厚型心肌病(HCM)是一种最常见的遗传性心脏病，属常染色体显性遗传，临床表现为心室肌肥厚(尤其是室间隔非对称性肥厚)、心律失常以及运动耐量受损及猝死。

TTN基因是肌联蛋白编码基因，表达于心肌和骨骼肌，蛋白分子量大，长度跨越肌节的1/2，是一种重要的结构蛋白。TTN基因突变可导致扩张型心肌病、HCM及多种心肌病。致病突变的类型主要为截短变异。

从分子水平揭示与TTN基因相关的肥厚型心肌病的发病机制，能够肥厚型心肌病的临床治疗提供理论依据，但是目前仍存在大量未知的TTN基因突变位点，进一步发现新的TTN基因的突变位点将有助于进一步研究肥厚型心肌病，对肥厚型心肌病的早期诊断，或者辅助临床判断具有重要意义。

发明内容

本发明的目的是针对肥厚型心肌病，提供一种突变的TTN基因及肥厚型心肌病检测试剂盒。

本发明提供的技术方案如下：

一、本发明提供一种突变的TTN基因，在基因组位置chr2:179610658处，碱基T突变为碱基G；参考基因组版本是GRCh37。

优选地，在基因组位置chr2:179610620-chr2:179610669处，突变的TTN基因的序列为SEQ ID NO:2。

二、本发明还提供了肥厚型心肌病检测试剂盒，包括用于扩增突变的TTN基因的引物。

优选地，引物的序列为SEQ ID NO:5和SEQ ID NO:6。

三、本发明的原理和有益效果在于：

本发明公开的突变的TTN基因可以作为临床辅助诊断肥厚型心肌病的生物标志物，对肥厚型心肌病的早期诊断，或者辅助临床判断具有重要意义；基于突变的TTN基因开发的检测试剂盒，可以检测出具有突变的TTN基因的患者，为受试者提供优生优育指导和遗传咨询，减少患儿出生。

附图说明

图1为实施例1的家系图；

图2为实施例1中先证者的Sanger测序图；

图3为实施例1家系中先证者母亲的Sanger测序图。

具体实施方式

下面通过具体实施方式进一步详细说明：

实施例1-先证者验证实验

样本来源：中国医学科学院阜外医院，在先证者(男，46岁)及其家属自愿签署知情同意书的前提下，寄送5-10mL全血样本，建立病历资料库，详细记录先证者病情、家系情况等资料。本研究已得到本单位伦理委员会批准。

采用Sanger测序法对先证者及其家属的TTN基因进行基因检测，具体步骤如下：

S1、提取基因组DNA；

采用江苏百世诺医疗科技有限公司的磁珠法全血基因组DNA提取试剂对先证者及其家属的人类全血EDTA抗凝样本进行全基因组DNA的提取，对DNA的浓度和纯度进行检测。

S2、准备PCR反应体系：

设计包含目的片段的特异性扩增引物：

上游引物(TTN-133379-E46P8F，SEQ ID NO:5)：5'TTGAAATGCCTCCTCGCTT 3'；

下游引物(TTN-133379-E46P8R，SEQ ID NO:6)：5'CCATCTTTGTACCAGTAAACCGT 3'；

长度：526bp。

扩增试剂使用江苏康为世纪生物科技有限公司生产的2×Taq Master Mix(Dye)。扩增体系：2×Taq Master Mix(Dye)25μL；上下游引物(10μM)各1μL；DNA模板<0.5μg；用ddH₂O补至50μL。

PCR扩增条件：94℃预变性2min；95℃变性32s，61℃退火25s，70℃延伸30s，共32循环。70℃终延伸2min。

产物检测：取2μL的PCR产物，使用1.5％的琼脂糖凝胶电泳检测PCR产物，选用1000bp Marker作为参考，检测验证扩增产物为预期的大小。

S3、采用3730XL Genetic Analyzer全自动测序仪对PCR产物进行测序。从NCBI(https://www.ncbi.nlm.nih.gov/)数据库获得参考序列和测序结果进行比对。

实验结果：

(1)本实施例发现先证者携带突变的TTN基因，具体检测结果如下表1所示：

表1突变的TTN基因的具体检测结果

基因

基因组位置

转录本号

碱基改变

氨基酸改变

参考基因组版本

外显子号

TTN

chr2:179610658

NM_133379

c.16469T>G

p.Leu5490Ter

GRCh37/hg19

Exon46

在基因组位置chr2:179610620-chr2:179610669处，野生型TTN基因的序列为SEQID NO:1：TTTAAGCAGTTTAATGGAAGAATTGGTCTTAAAGAGCAACTACACAGACA，T为基因组位置chr2:179610658处突变前碱基。

在基因组位置chr2:179610620-chr2:179610669处，突变的TTN基因的序列为SEQID NO:2：TTTAAGCAGTTGAATGGAAGAATTGGTCTTAAAGAGCAACTACACAGACA，G为基因组位置chr2:179610658处突变后碱基；

野生型TTN基因编码DNA的参考序列为SEQ ID NO:3：

ATGACAACTCAAGCACCGACGTTTACGCAGCCGTTACAAAGCGTTGTGGTACTGGAGGGTAGTACCGCAACCTTTGAGGCTCACATTAGTGGTTTTCCAGTTCCTGAGGTGAGCTGGTTTAGGGATGGCCAGGTGATTTCCACTTCCACTCTGCCCGGCGTGCAGATCTCCTTTAGCGATGGCCGCGCTAAACTGACGATCCCCGCCGTGACTAAAGCCAACAGTGGACGATATTCCCTGAAAGCCACCAATGGATCTGGACAAGCGACTAGTACTGCTGAGCTTCTCGTGAAAGCTGAGACAGCACCACCCAACTTCGTTCAACGACTGCAGAGCATGACCGTGAGACAAGGAAGCCAAGTGAGACTCCAAGTGAGAGTGACTGGAATCCCTACACCTGTGGTGAAGTTCTACCGGGATGGAGCCGAAATCCAGAGCTCCCTTGATTTCCAAATTTCACAAGAAGGCGACCTCTACAGCTTACTGATTGCAGAAGCATACCCTGAGGACTCAGGGACCTATTCAGTAAATGCCACCAATAGCGTTGGAAGAGCTACTTCGACTGCTGAATTACTGGTTCAAGGTGAAGAAGAAGTACCTGCTAAAAAGACAAAGACAATTGTTTCGACTGCTCAGATCTCAGAATCAAGACAAACCCGAATTGAAAAGAAGATTGAAGCCCACTTTGATGCCAGATCAATTGCAACAGTTGAGATGGTCATAGATGGTGCCGCTGGGCAACAGCTGCCACATAAAACACCTCCCAGGATTCCTCCGAAGCCAAAGTCAAGATCCCCAACACCACCGTCTATTGCTGCCAAAGCACAGCTGGCTCGGCAGCAGTCCCCATCGCCCATAAGACACTCCCCTTCCCCGGTCAGACACGTGCGGGCACCGACCCCATCTCCGGTCAGGTCCGTGTCTCCAGCAGCAAGAATCTCCACATCCCCCATCAGGTCTGTTAGGTCTCCATTGCTCATGCGTAAGACTCAGGCATCCACCGTGGCCACAGGTCCTGAAGTGCCTCCCCCTTGGAAGCAAGAGGGCTACGTGGCCTCCTCATCTGAGGCTGAGATGAGAGAGACAACGCTGACAACCTCTACTCAGATCAGGACAGAAGAGAGATGGGAAGGGAGATACGGTGTCCAGGAGCAAGTGACCATCAGTGGTGCTGCGGGTGCTGCCGCCAGTGTGTCGGCCAGTGCTAGCTACGCAGCAGAGGCTGTTGCCACTGGTGCTAAAGAGGTGAAACAAGATGCTGACAAAAGTGCAGCTGTTGCGACTGTTGTTGCTGCCGTTGATATGGCCAGAGTGAGAGAACCAGTGATCAGCGCTGTAGAGCAGACTGCTCAGAGGACAACCACGACTGCTGTGCACATCCAACCTGCTCAAGAACAGGTAAGAAAGGAAGCGGAGAAGACTGCTGTAACTAAGGTAGTAGTGGCCGCCGATAAAGCCAAGGAACAAGAATTAAAATCAAGAACCAAAGAAGTAATTACCACAAAGCAAGAGCAGATGCACGTAACTCATGAGCAGATAAGAAAAGAAACTGAAAAAACATTTGTACCAAAGGTAGTAATTTCCGCAGCTAAAGCCAAAGAACAAGAAACTAGAATTTCTGAAGAAATTACTAAGAAACAGAAACAAGTAACTCAAGAAGCAATAAGACAGGAAACTGAGATAACTGCTGCATCCATGGTGGTAGTTGCCACTGCAAAGTCCACAAAACTAGAAACAGTCCCGGGAGCTCAAGAAGAAACTACCACACAACAAGATCAAATGCACCTAAGTTATGAAAAGATAATGAAGGAAACTAGGAAAACAGTTGTACCTAAAGTCATAGTTGCCACACCCAAAGTCAAAGAACAAGATTTAGTATCAAGAGGTAGAGAAGGCATTACTACCAAAAGAGAACAAGTGCAAATAACTCAGGAGAAGATGAGAAAGGAAGCCGAGAAAACTGCCTTGTCTACAATAGCAGTTGCTACTGCTAAAGCCAAAGAACAAGAAACAATACTGAGAACTAGAGAAACTATGGCTACTAGACAAGAACAAATCCAAGTTACCCATGGAAAGGTGGACGTTGGAAAAAAGGCTGAAGCTGTAGCAACAGTTGTTGCTGCAGTAGACCAGGCCCGAGTCAGAGAGCCCAGAGAGCCTGGGCATCTTGAAGAATCCTATGCTCAGCAGACCACTTTGGAGTACGGATATAAGGAACGCATTTCCGCCGCAAAGGTAGCTGAGCCTCCCCAACGTCCAGCCTCAGAACCCCACGTTGTCCCTAAAGCAGTCAAGCCTAGAGTAATCCAGGCTCCTTCTGAGACTCATATCAAAACTACTGATCAAAAGGGAATGCACATATCATCACAGATCAAGAAAACTACAGATCTAACAACGGAAAGATTAGTCCATGTGGATAAACGCCCCCGCACAGCTAGCCCTCACTTTACTGTTTCAAAAATTTCTGTTCCTAAGACAGAACATGGATATGAGGCATCAATAGCCGGTAGTGCTATTGCCACATTACAAAAAGAGTTGTCAGCCACATCTTCTGCTCAGAAGATCACCAAATCGGTGAAGGCTCCTACTGTGAAGCCCAGTGAGACTAGAGTAAGGGCAGAGCCCACACCCTTGCCACAGTTCCCCTTCGCTGACACACCAGATACTTACAAGAGTGAAGCTGGCGTTGAGGTGAAAAAGGAAGTAGGGGTGAGCATCACTGGCACCACCGTCCGTGAAGAGCGCTTTGAAGTACTGCACGGACGCGAAGCCAAGGTAACAGAAACAGCAAGAGTACCAGCACCTGTTGAAATTCCTGTTACTCCACCAACTTTGGTCTCGGGCTTAAAAAATGTGACTGTCATAGAAGGTGAATCTGTCACCTTGGAGTGCCACATCTCTGGATACCCATCCCCGACAGTGACATGGTACAGGGAAGACTACCAAATCGAAAGTTCCATTGACTTCCAGATAACCTTCCAGAGTGGAATTGCTCGTCTTATGATTCGCGAAGCATTTGCGGAAGACAGCGGGCGATTTACTTGCAGTGCTGTAAATGAGGCTGGAACCGTCAGCACATCCTGCTATCTGGCTGTGCAGGTGTCAGAAGAATTTGAAAAGGAAACCACAGCCGTGACTGAGAAATTTACTACAGAAGAGAAACGCTTTGTTGAGTCAAGAGATGTGGTTATGACTGATACTAGCCTCACAGAGGAACAAGCAGGGCCTGGAGAACCTGCCGCGCCTTACTTTATTACAAAACCAGTGGTCCAGAAACTGGTGGAAGGTGGGAGCGTGGTGTTTGGATGCCAAGTTGGCGGCAACCCAAAGCCCCATGTATACTGGAAAAAATCTGGTGTTCCTCTAACCACTGGATACAGATACAAAGTGAGTTACAACAAACAAACCGGTGAATGCAAGCTGGTGATTTCTATGACTTTTGCTGATGATGCTGGAGAATACACTATTGTTGTTCGCAATAAGCATGGAGAAACTTCTGCATCTGCTTCCTTGCTTGAAGAAGCTGATTATGAGTTACTGATGAAGTCCCAGCAAGAAATGCTTTATCAGACACAAGTGACTGCATTTGTTCAAGAACCTAAAGTTGGAGAAACAGCACCTGGATTTGTATACTCTGAGTATGAAAAAGAGTATGAAAAAGAACAAGCCTTAATTAGGAAGAAAATGGCCAAAGATACTGTAGTGGTCAGAACTTATGTAGAAGATCAGGAATTCCATATTTCTTCCTTTGAAGAGAGACTTATTAAAGAAATTGAATATAGAATAATAAAGACTACATTAGAAGAACTTCTTGAAGAAGATGGAGAAGAAAAGATGGCAGTTGACATTTCTGAATCTGAAGCTGTTGAATCAGGATTTGATTCAAGAATCAAGAATTATAGAATTCTTGAGGGGATGGGTGTCACTTTTCATTGCAAGATGTCTGGATATCCATTACCAAAGATTGCTTGGTACAAAGATGGCAAGCGCATCAAACATGGAGAAAGATACCAAATGGACTTTCTACAAGATGGCAGAGCTAGTCTGCGTATACCTGTTGTTCTTCCAGAAGATGAAGGAATCTACACTGCATTTGCCAGCAATATTAAAGGAAATGCAATTTGCTCAGGGAAATTGTATGTGGAGCCTGCTGCACCACTTGGAGCTCCGACTTACATTCCCACACTAGAGCCAGTGAGCAGAATCAGATCTCTCTCTCCACGTTCAGTGAGCAGGTCTCCTATACGCATGTCTCCTGCACGGATGTCACCTGCAAGGATGTCTCCTGCACGGATGTCCCCTGCAAGAATGTCCCCTGGACGTAGGCTGGAGGAGACAGATGAGTCACAACTTGAGAGACTATATAAACCAGTCTTTGTGTTAAAACCTGTTTCTTTCAAATGTTTAGAAGGGCAAACTGCCAGATTTGACTTAAAGGTTGTTGGTAGACCTATGCCAGAGACGTTCTGGTTTCATGATGGCCAGCAAATTGTCAATGACTATACCCATAAAGTAGTCATTAAAGAAGATGGTACTCAATCACTAATTATTGTCCCTGCCACACCCAGTGATTCTGGGGAATGGACTGTGGTTGCCCAAAACAGGGCAGGCAGATCTTCAATTTCAGTGATTTTAACTGTGGAAGCTGTGGAACATCAGGTAAAACCGATGTTTGTAGAAAAACTGAAAAATGTCAATATAAAGGAAGGTTCCCGACTTGAAATGAAAGTCAGAGCTACGGGTAACCCCAACCCTGACATTGTATGGTTGAAAAACAGTGACATCATTGTGCCTCATAAATATCCCAAAATCAGAATTGAAGGAACCAAGGGAGAAGCTGCCCTTAAAATCGATTCCACTGTCAGCCAAGATTCTGCCTGGTATACTGCGACTGCTATTAATAAAGCTGGCAGAGACACTACAAGATGCAAAGTAAATGTTGAAGTTGAGTTTGCAGAGCCTGAGCCAGAGAGAAAGTTAATCATCCCACGGGGGACATATAGAGCAAAGGAGATTGCAGCCCCAGAACTGGAGCCCCTCCATTTGCGATATGGCCAAGAGCAATGGGAAGAAGGTGATCTCTATGACAAAGAGAAACAACAGAAACCATTTTTCAAGAAAAAACTCACTTCCTTAAGACTTAAGCGCTTTGGGCCTGCCCACTTTGAATGCAGGCTAACACCCATTGGTGACCCAACGATGGTGGTGGAGTGGCTCCATGATGGAAAGCCACTTGAAGCAGCCAACAGGCTCCGTATGATCAATGAATTTGGGTACTGCAGCCTTGATTATGGCGTTGCATATTCTAGAGACAGTGGTATCATTACTTGCAGAGCCACTAACAAATATGGAACAGATCACACATCTGCTACCCTTATTGTTAAAGATGAGAAAAGTCTTGTGGAAGAATCCCAATTGCCTGAGGGGAGGAAAGGCTTACAGAGAATTGAAGAATTAGAGAGAATGGCTCATGAAGGTGCACTTACAGGTGTAACAACAGATCAGAAAGAAAAGCAAAAGCCAGACATTGTCTTGTACCCAGAGCCAGTTAGAGTACTTGAAGGGGAGACTGCAAGGTTCCGCTGCAGGGTAACAGGCTACCCTCAGCCCAAAGTCAACTGGTACCTCAATGGACAGCTCATCCGCAAAAGCAAAAGGTTCAGAGTTCGCTATGATGGTATCCATTACCTGGACATCGTGGACTGCAAATCATATGACACAGGTGAAGTGAAGGTCACCGCGGAAAATCCTGAAGGTGTGATAGAGCATAAAGTGAAGCTTGAGATTCAACAGAGGGAAGATTTTAGGTCTGTCCTTAGGAGAGCTCCTGAACCAAGGCCTGAGTTTCACGTACATGAACCAGGAAAGCTTCAGTTTGAAGTACAAAAAGTGGATAGACCTGTTGACACCACTGAAACCAAAGAAGTTGTGAAGTTGAAAAGGGCTGAAAGAATTACCCATGAAAAAGTGCCTGAAGAGTCGGAAGAGCTGCGCAGTAAATTCAAGCGCAGAACAGAAGAGGGCTATTATGAAGCCATTACCGCTGTGGAGCTCAAGTCTCGAAAGAAGGATGAATCCTATGAGGAACTCCTCAGGAAGACAAAAGATGAACTTCTCCACTGGACCAAAGAGTTAACTGAAGAGGAAAAGAAAGCTCTTGCCGAAGAAGGCAAAATCACGATTCCAACTTTTAAACCTGACAAGATTGAACTAAGTCCTAGTATGGAGGCTCCAAAAATCTTCGAAAGAATCCAGAGCCAAACAGTGGGCCAAGGATCTGATGCACACTTCCGGGTCAGAGTCGTGGGGAAACCAGACCCCGAATGTGAATGGTACAAAAATGGTGTCAAAATTGAACGGTCTGACCGGATCTACTGGTACTGGCCCGAAGACAATGTTTGTGAATTGGTCATAAGAGATGTGACTGCTGAGGACTCTGCCAGCATCATGGTAAAAGCCATCAACATAGCTGGAGAAACCTCCAGTCACGCATTCTTACTTGTCCAAGCCAAGCAATTGATCACTTTCACACAGGAATTACAAGATGTTGTTGCTAAGGAAAAAGACACTATGGCAACCTTTGAATGTGAAACTTCAGAACCATTTGTCAAAGTGAAATGGTATAAAGATGGTATGGAGGTTCATGAGGGAGATAAATACAGGATGCACTCTGACAGAAAGGTTCACTTCCTCTCCATACTGACCATTGATACGTCTGATGCTGAAGATTACAGCTGTGTACTTGTGGAAGATGAAAATGTCAAAACGACTGCTAAACTTATTGTTGAAGGTGCAGTTGTTGAGTTTGTGAAAGAACTTCAGGACATAGAAGTTCCAGAATCATATTCAGGAGAATTAGAGTGCATTGTATCCCCAGAAAATATAGAAGGAAAATGGTATCATAATGATGTGGAGCTTAAATCCAATGGCAAATATACAATTACATCTCGTCGTGGACGTCAGAACCTCACGGTCAAGGATGTAACCAAGGAGGACCAGGGAGAATACAGCTTTGTCATCGACGGGAAAAAGACAACCTGTAAATTAAAGATGAAACCCCGCCCCATTGCTATCCTACAAGGACTTAGTGACCAAAAAGTCTGTGAGGGTGACATTGTTCAGCTTGAAGTTAAAGTCTCCTTGGAAAGTGTGGAAGGCGTCTGGATGAAAGACGGCCAAGAAGTGCAGCCCAGTGACAGGGTTCACATTGTGATAGACAAACAATCTCATATGCTGCTCATTGAAGACATGACTAAGGAAGATGCTGGAAATTACTCTTTCACCATTCCAGCCCTTGGCCTCTCCACCAGTGGGCGTGTCTCTGTCTATAGTGTGGACGTGATAACACCTCTAAAAGATGTTAATGTGATTGAAGGCACCAAGGCTGTGCTTGAATGTAAGGTGTCAGTCCCTGATGTGACTTCTGTTAAGTGGTACTTAAATGATGAACAAATCAAGCCTGATGACCGTGTACAGGCCATTGTGAAAGGTACTAAACAGCGACTAGTCATTAACCGAACTCATGCTTCAGACGAAGGACCTTACAAGCTGATAGTTGGCAGAGTTGAAACCAACTGTAATCTCTCTGTAGAAAAAATTAAAATTATCAGAGGTCTTCGTGACCTTACCTGTACAGAAACTCAAAATGTGGTGTTTGAGGTTGAGCTGTCCCACTCTGGAATTGATGTCCTGTGGAATTTTAAGGACAAGGAAATCAAGCCCAGTTCTAAATATAAAATTGAAGCACATGGAAAAATATATAAATTGACAGTTCTAAATATGATGAAAGATGATGAAGGAAAATACACATTTTACGCGGGAGAAAATATGACATCTGGAAAACTTACTGTGGCAGGTGGGGCCATCTCCAAGCCACTCACAGATCAGACCGTAGCTGAATCCCAGGAAGCTGTGTTTGAATGTGAAGTTGCCAACCCAGATTCCAAAGGCGAATGGTTGAGGGATGGCAAACACCTACCACTGACTAACAACATCAGAAGTGAGTCTGATGGCCACAAAAGGAGACTTATCATTGCTGCCACCAAATTAGATGACATTGGAGAATATACCTACAAGGTGGCCACCTCCAAAACATCTGCCAAACTCAAAGTTGAAGCTGTCAAAATTAAGAAGACTCTGAAGAACCTCACAGTGACAGAAACACAGGATGCTGTTTTCACTGTCGAGCTTACACACCCTAATGTCAAAGGTGTCCAGTGGATCAAAAATGGAGTTGTGCTGGAATCCAATGAAAAGTATGCTATCTCTGTCAAAGGAACAATTTACTCTCTGAGGATTAAAAACTGTGCCATCGTGGATGAGTCTGTTTATGGCTTCAGGCTTGGAAGGCTTGGAGCCAGTGCCAGACTGCACGTGGAGACTGTCAAGATCATTAAAAAGCCAAAGGATGTGACAGCCTTGGAAAATGCCACTGTTGCCTTTGAAGTTAGTGTTTCCCATGACACTGTTCCAGTAAAATGGTTCCATAAGAGTGTGGAAATTAAGCCAAGTGACAAACACAGACTGGTCTCAGAAAGGAAAGTCCACAAGCTGATGCTGCAGAACATCTCCCCCTCAGATGCTGGGGAATACACAGCTGTGGTCGGGCAATTGGAATGCAAAGCAAAACTGTTTGTGGAGACATTACATATTACAAAAACCATGAAAAATATCGAGGTGCCTGAGACCAAAACTGCCTCTTTTGAGTGTGAGGTGTCCCACTTCAATGTCCCTTCCATGTGGCTGAAGAATGGTGTGGAAATTGAGATGAGTGAAAAGTTCAAGATAGTTGTGCAGGGAAAACTCCATCAGCTGATCATCATGAACACCAGCACAGAGGACTCGGCAGAATACACATTTGTCTGTGGCAATGACCAAGTCAGTGCCACCCTGACAGTCACCCCAATCATGATTACTTCCATGCTGAAAGACATCAACGCTGAAGAAAAAGACACTATTACTTTTGAGGTGACAGTGAACTATGAAGGCATCTCTTACAAATGGTTAAAGAATGGTGTGGAAATCAAATCAACTGACAAGTGCCAGATGAGAACCAAAAAGCTCACACACTCACTGAACATCAGGAATGTTCACTTTGGGGATGCTGCTGACTACACCTTTGTGGCTGGAAAAGCAACATCAACAGCCACACTTTATGTGGAAGCTCGTCATATAGAATTTAGGAAACACATTAAGGACATTAAGGTACTGGAGAAGAAGCGAGCCATGTTTGAATGTGAAGTTTCTGAACCTGACATCACTGTACAGTGGATGAAAGATGACCAGGAACTGCAGATCACAGACAGAATAAAGATTCAGAAGGAGAAATATGTCCACCGCCTTCTGATCCCATCCACCCGGATGTCTGATGCTGGGAAGTACACAGTGGTGGCAGGAGGCAACGTGTCAACTGCAAAACTCTTTGTAGAAGGCAGAGATGTTCGCATCCGAAGTATTAAAAAGGAGGTTCAGGTCATTGAGAAACAGCGTGCTGTTGTTGAATTTGAGGTCAATGAAGACGATGTTGATGCCCACTGGTATAAAGATGGCATTGAAATCAATTTCCAAGTTCAAGAACGACACAAATATGTAGTGGAAAGAAGAATCCACCGAATGTTTATCTCTGAGACCAGACAGAGCGATGCAGGAGAATACACCTTTGTGGCAGGAAGGAACAGGAGTTCTGTCACTCTCTATGTCAATGCTCCTGAACCGCCCCAAGTTCTGCAGGAGCTCCAGCCTGTCACTGTGCAGTCTGGCAAGCCTGCCCGCTTCTGTGCCGTGATATCCGGAAGACCACAGCCCAAAATTTCCTGGTACAAGGAAGAGCAGCTGCTTTCCACTGGCTTCAAGTGCAAATTTCTTCATGATGGGCAAGAATACACGCTTTTGCTAATTGAAGCCTTCCCAGAGGATGCGGCAGTCTATACCTGTGAAGCCAAGAATGACTATGGTGTTGCCACAACATCAGCTTCACTCTCAGTGGAAGTTCCAGAAGTTGTGTCTCCTGATCAGGAAATGCCTGTTTATCCACCTGCCATCATCACCCCGCTTCAGGACACTGTCACTTCTGAAGGGCAGCCAGCCCGTTTTCAATGCCGGGTTTCTGGAACAGATCTAAAAGTGTCGTGGTACAGCAAAGACAAGAAAATCAAGCCATCTCGGTTCTTTAGAATGACTCAATTTGAAGACACTTATCAACTGGAAATTGCCGAAGCTTATCCAGAAGATGAAGGAACTTACACGTTTGTTGCTAGTAATGCTGTAGGCCAAGTATCAAGCACAGCCAACCTGAGTCTGGAAGCTCCTGAATCAATTTTGCATGAGAGGATTGAACAAGAGATTGAGATGGAAATGAAAGAATTATTCTCTGAGGGGGAATCTGAACATTCAGAAAGGGATACACGTGACGCCTTTTCAGATTCTGAAGACATAGACCACAAATCCATGGCTGCTAAAAGATATGCAAGTAGAATATCATCTACAAGCTCCTGGCCTGAATATTTTAAGCCTTCTTTTACCCAGAAACTTACATTTAAATATGTTTTAGAGGGTGAACCGGTTGTTTTTACATGTAGATTAATTGCCTGTCCAACTCCAGAAATGACTTGGTTTCATAACAATCGGCCCATCCCAACAGGTCTTCGTCGGATTATAAAAGCTGAGAGTGATTTACACCATCACTCTTCCAGCTTAGAGATTAAAAGGGTCCAAGACAGAGATTCTGGAAGTTATAGGTTACTAGCAATTAATAGTGAAGGGTCTGCAGAATCAACTGCATCATTGCTTGTTATCCAAAAAGGGCAAGATGAGAAATATTTAGAATTTCTGAAAAGAGCAGAACGGACACATGAAAATGTGGAGGCTTTAGTTGAAAGGGGAGAAGATAGGATAAAGGTTGACCTGAGGTTTACTGGCTCTCCCTTTAACAAAAAACAAGATGTGGAACAAAAGGGAATGATGAGAACTATACATTTTAAGACAATGAGTTCTGCCAAGAAAACAGATTACATGTATGATGAAGAATATTTAGAAAGTAAATCTGACATAAGAGGTTGGCTTAATGTAGGTGAAAGTTTCCTGGACAAGGAGACCAAAGTGAAGTTGCAACGTTTAAGGGAGGCTAGAAAAACATTAATGGAGAAAAAGAAATTATCTCTTTTAGATACGTCTTCTGAAATAAGCTCAAGAACTTTGAGAAGTGAAGCTAGTGATAAAGATATTCTGTTCTCTAGAGAGGACATGAAAATCAGATCTATGTCTGATCTAGCTGAAAGTTATAAGGTAGATCATTCAGCTGAGAGTATTGTGCAAAATCCACATGCCCTTTCTAATCAAATGGATCAAAATATAGAATCTGAGGAACTTCCCACAAGCTTTCAAACTATTGTTGATGAAGAAATTTTCCAGACTGAAATAAGAATGAGCCAAGAAGCACTGGTAAAGGAAAGTCTACCAAAAGACCATTTATATGGTGAAATTCTAGTAAATGAAAATACCCAAGCAAGAGGACAGCTGGAAGAAATTATGGCCAATACTACAATTGGAGAGTCATCCACATATATCACTAATGTATGTGAGAAGGAGGAAGTATATGAGACTCCTGAAAATGTGTCTCAAGCTATTACACCACATGCCAGCGAATCTTTTGGTACACTTGTAAATGTTGAAGAAAGTGAAGAAATAGCTAGTGAAAGAATAAAAAAGGATGATTTGAGAGAATTACAACTCTCTGCTTCTACACGAATTGATGAATTCAAAACCGAACAGAAGGAAGAAAACATGAGATTTTTTGAAAATTCTTTTCGAAAACGCCCACAACGTTGCCCACCTTCATTTCTTCAAGAAATTGAATCTCAAGAAGTTTATGAAGGTGACAGTTGTAATTTTGTGTGTCATTTTCAAGGATATCCTCAACCTATAGTGACGTGGTATAACAATGACATGCCAATCCCACGTAATCAAAACTTTATCATTCATTCGTTGGAAAACTATTCAATATTAACTCTTTCATCTGTTCATCATCAGAATGAAGGTTCTATTACTTGTGTGCTATTTAACCAATATGGAACAGTAAAAACAACCAGTATGCTTAAAGTGAAAGCAAAACAAAAACATGATGTCAAAGCACATAAAGTCCCAGTGTTCCATGACTACTTGGATGAGGAAGAAGAGTTAGCATTGGTGTTTGACCAAGCAAAAGGCGCCCATCCATCTATGAGTCAAGAGGGCCAAACAAATCTTCATTTGTTAAAAACTAACCCACCAGTTCCTCCCTCTGGAGACACAGAATTGCTTTCCTTTCCTGTAGAAATTCAGGTAACAGCAGCTACTCCTATCCCAGAACAGGATAAAGAGTCTAAAGAAGTGTTTCAAACTGAGGAGCTGGAACCTAAAGCAATGCCTCAAGATCAAGTTACTCAATCACCAAAACACAGATTTGTATTTTTGTCTGATATTACTAATGAACCACCAAAAATGTTACAAGAAATGCCAAAGCATGCCAGGTGTAGAGAAGGGGATTCCATCATTCTTGAATGTTTAATATCTGGTGAGCCCCAGCCAGTTGTAACATGGTTTCAAAATGGAGTCCTTTTAAAGCAGAACCAGAAGTTTCAGTTTGAAGAAGTTAATTGTAGCCACCAATTATATATTAAGGATGTTAATTCTCAAGATTCTGGAAAATATAAATGTGTTGCTGAAAACAATTCAGGGGCAGTTGAAAGTGTTTCAGATCTAACAGTGGAGCCTGTCACTTATAGAGAAAATAGTCAATTCGAAAATATTGGTGAAATTTATGGAAAATATTCCAGAGATCAGCAACTGCAAGACCAGGGAGAATCTGTAAGGGCACATTTTTATGATTATCCAGCTGGTCCCTTTACTCCCTGGACAAATGTAAAAGAATATTCAGTAAGGGACTATTTTCAAAGCCTTGAGACTATTGAGCAAATAGACCAGAAAGAGCAGGTGCGTTGCATACCTTCTAGAGAAAAAATTCCCAGATTTGTGCATGGTGCTTCAAGAACCATAAAAATCAGCAAGCCCATCAGGGCTGAATTCATACAATGTCAGGCTGAAGGGAAAGAGAGACATGTAAGTGAAAAATCAAAGCTGCACCAAGCAGAGGGTACTGTTTATCCATTTGTTGATGATTTCAGTGATGTCACTATTAAGAAAGAAATAAGAAATAATTTTGGAAAACTTGGTAGATCAGAAAAGGAAAATGTACAAGAATGTGCCCAAAGTGACTATTTACCAAATATTCACTCTGAGAGAATTTCTGACAGTTACAATACAAAAGATTCATCTGCCATTGTATATGAAGAATCCCTTGGTGAAGAGATACACTACCCGGGGAAAAAGGTGAAGCATAGAATTATCGAATTTGAAAAATTACATGTAGAAAAAGGAGTTCTAGAAAAAAGACCTACCAGAACATCAATTGTTAATCCTCCTCAAAAGAAGATTGATGACAAAGCCTTTTCATTAAAGCAAAGAGAATCAAGATCAAGCAATCTAAATGCAAATATGTATCAGGCAGAGAAAATGTCTCCAAATACTGAATCAGATTCATCTAACATTGCAATAAATTTAAAGCTGCTTTCCTCTCAAACTCATAAAGAATTTGACGCACAAGAAAGGGAACAACAGGAAAAAATAAGTCTTATAGATAAACCTGCAATTTCTAAAAGAGCTGAACATGAATCACCTATTACATTTGACTTAAAGCAGTTTCACACTCAAATAAAACACACAGATGTGAAATTCCAAGAATTAGATAGTGGTCAACCAGAAGAAGCTTATTTTAAAATCCAACATCCTGCTGACACTGAGAACATTGTATTTGATCTAAAACAAATGTATTCTCATATAGGAGATCCAGCTCTGGAGTTCCAAGGGCAAGAAACTAGGGAACAGCAGGAAATACATTATAAAGAAAAAATTCCTAGCCCTGAAACGTTACAACCTGACACACACAATATCTCTAAAAGTGTGCAAAATAATGTATTTGCCAGTCAAGAAATTTCTTCCAGTCAAGAGCTTTCAAATAGAACTATGGTGGAGAAAAGTAGTATTGATGAAAATTCCATTTCTTTAGAAAAAGAAGTCCGACATGTACAGGAACAAAACTTAGACATTTTAAAAACTGATCTTTCTCTTAAATCCTTTTCTGAAGAAATCTATAGTGAATCATGTGCCCTACTTCCAACCTCATCTGCAGATATAGAAGAAACTGATCTTTCTGAGAAAAGTTGTCCTCTAGAAAATGGAGGCAGAAGTTCCATCTCACATTTGAAAAAAGCAGCAAGTGAGGAAAAGCCTTTAGGGGTTGGTGAAATGGAAGAAGAATGCACTCTAGAACCAGAGTTGGCAGCATTTCCAAAGCAGGATGGTGGGACACAGGAATATACAGATGCCACTTTGGAAGACCACAGAGGTGATGTTCAGGAAGCTGACACACTCCATAGACAGCTCTCCCTGAGTCAGTGCTTCCCACTCTTGATGACTGAAGAACAACAGAATCCAGGTGAACAAATAAGTACAAACATTCATGCCTCTGGAGAAGAAAAATGTTATGAAGAAGTTCAAGTTCAGAATGAAGCTTCTTTCTCCACTTTAGAAGGAGAAATGATAGAAACTAGTTTTTCTCAAAATATTCCTAAATTAGATGAGGCACATACCACTGAGGCAGCAGAATCTGAGACCTCCCTAACACAATATTTACTTGCTGCTGGAAAGCGTGAGGTTCCTGAAACTAAAGACACCAGAGACCAGGCAAAGCTTGTCCAGAGTGAATCAATCACTTCAATGGAGGTGGAAGAAGTAACTTTCAACACTGTGTATGAATACTACAACCAGAAACAGGAATCACTAGGTCGTCCACTTTCTCCTGAGTCTGACATTTCCATTGGTGTGGGAAGTACAACCAGTGAAGAAATATCTGAGTTAGATCAGTTTTATACCCCACCATCATCTGTTGAATATTTTGAATCTCCAAAGTCCCCTGACTTATATTTTAATCCTTCAGATATAACTAAACAATCCTCAATACATTCAGGAGGTGAGACAGTTGAAAGATATTCCACACCTTTAGGGGAAGTTGCTGAAAGATATTCAACACCTTCCGAAGGTGAGGTAGGAGAAAGATACTCCACACCCCCAGGGGAGACACTAGAGAGATACTCCACACCTCCAGGAGAGACTCTAGAGAGATACTCCACACCCCCAGGAGAGACTCTAGAGAGATATTCCACACCCCCAGGAGAGACTCTGGAGAGATACTCCACACCCCCAGGAGAGACTCTAGAGCGATATTCCACACCCCCAGGGGAGGCACTAGAGAGATATTCTATTCCTACTGGAGGACCAAACCCCACTGGTACTTTTAAAACATATCCATCAAAAATAGAAAGGGAAGACGGTACACCAAATGAGCATTTCTACACACCTACAGAAGAGAGGGGTTCAGCTTATGAAATATGGCGTTCCGATTCATTTGGTACACCCAATGAAGCCATTGAGCCAAAAGACAATGAAATGCCTCCATCTTTTATTGAACCTCTGACCAAAAGGAAGGTATATGAAAACACAACACTAGGCTTCATTGTTGAAGTTGAAGGTCTTCCAGTTCCTGGTGTGAAATGGTATCGAAATAAATCTTTACTAGAGCCAGATGAAAGAATCAAAATGGAAAGAGTGGGTAATGTGTGTTCACTGGAAATTTCTAACATTCAAAAAGGAGAAGGGGGAGAGTACATGTGTCATGCTGTAAACATCATAGGGGAAGCAAAGAGCTTTGCAAATGTAGACATAATGCCCCAGGAAGAAAGAGTGGTGGCACTACCACCTCCAGTAACACATCAGCATGTCATGGAGTTTGATTTGGAACACACCACATCATCAAGAACACCTTCTCCTCAAGAAATTGTCCTGGAAGTTGAATTAAGTGAAAAAGACGTTAAAGAATTTGAGAAGCAGGTGAAAATAGTGACAGTTCCCGAATTTACTCCTGACCATAAAAGTATGATTGTGAGTCTAGATGTTCTTCCATTTAATTTTGTAGATCCAAATATGGATTCAAGGGAGGGAGAAGACAAAGAACTAAAAATTGATTTAGAAGTATTTGAAATGCCTCCTCGCTTTATAATGCCTATTTGTGATTTTAAAATTCCAGAAAATTCAGATGCTGTATTCAAATGTTCAGTCATAGGGATCCCGACTCCCGAAGTTAAGTGGTATAAAGAATATATGTGTATTGAGCCAGATAATATTAAATACGTGATTAGCGAGGAGAAGGGAAGTCACACTCTTAAAATTCGAAATGTCTGTCTTTCTGATAGTGCAACATACAGGTGCAGAGCTGTGAATTGTGTAGGAGAGGCTATCTGTCGGGGATTCCTCACCATGGGAGATTCTGAAATATTTGCTGTGATAGCAAAGAAAAGCAAAGTGACTTTAAGCAGTTTAATGGAAGAATTGGTCTTAAAGAGCAACTACACAGACAGTTTTTTTGAATTTCAGGTGGTGGAAGGGCCTCCCAGGTTTATCAAAGGTATTTCTGACTGTTATGCACCAATAGGTACAGCAGCATATTTTCAGTGCTTAGTTCGTGGCTCTCCAAGACCCACGGTTTACTGGTACAAAGATGGAAAATTAGTCCAAGGAAGAAGGTTCACTGTTGAGGAAAGTGGCACAGGGTTCCATAACCTGTTTATAACAAGCTTAGTAAAGAGTGATGAAGGAGAGTATAGGTGTGTAGCTACAAACAAATCAGGAATGGCTGAGAGCTTTGCAGCACTCACCTTAACTTAA，T为编码DNA的参考序列的第16469位突变前碱基。

c.16469T>G表示：与野生型TTN基因编码DNA的参考序列相比，第16469位点的碱基T突变为碱基G。

野生型TTN基因编码蛋白为SEQ ID NO:4：

MTTQAPTFTQPLQSVVVLEGSTATFEAHISGFPVPEVSWFRDGQVISTSTLPGVQISFSDGRAKLTIPAVTKANSGRYSLKATNGSGQATSTAELLVKAETAPPNFVQRLQSMTVRQGSQVRLQVRVTGIPTPVVKFYRDGAEIQSSLDFQISQEGDLYSLLIAEAYPEDSGTYSVNATNSVGRATSTAELLVQGEEEVPAKKTKTIVSTAQISESRQTRIEKKIEAHFDARSIATVEMVIDGAAGQQLPHKTPPRIPPKPKSRSPTPPSIAAKAQLARQQSPSPIRHSPSPVRHVRAPTPSPVRSVSPAARISTSPIRSVRSPLLMRKTQASTVATGPEVPPPWKQEGYVASSSEAEMRETTLTTSTQIRTEERWEGRYGVQEQVTISGAAGAAASVSASASYAAEAVATGAKEVKQDADKSAAVATVVAAVDMARVREPVISAVEQTAQRTTTTAVHIQPAQEQVRKEAEKTAVTKVVVAADKAKEQELKSRTKEVITTKQEQMHVTHEQIRKETEKTFVPKVVISAAKAKEQETRISEEITKKQKQVTQEAIRQETEITAASMVVVATAKSTKLETVPGAQEETTTQQDQMHLSYEKIMKETRKTVVPKVIVATPKVKEQDLVSRGREGITTKREQVQITQEKMRKEAEKTALSTIAVATAKAKEQETILRTRETMATRQEQIQVTHGKVDVGKKAEAVATVVAAVDQARVREPREPGHLEESYAQQTTLEYGYKERISAAKVAEPPQRPASEPHVVPKAVKPRVIQAPSETHIKTTDQKGMHISSQIKKTTDLTTERLVHVDKRPRTASPHFTVSKISVPKTEHGYEASIAGSAIATLQKELSATSSAQKITKSVKAPTVKPSETRVRAEPTPLPQFPFADTPDTYKSEAGVEVKKEVGVSITGTTVREERFEVLHGREAKVTETARVPAPVEIPVTPPTLVSGLKNVTVIEGESVTLECHISGYPSPTVTWYREDYQIESSIDFQITFQSGIARLMIREAFAEDSGRFTCSAVNEAGTVSTSCYLAVQVSEEFEKETTAVTEKFTTEEKRFVESRDVVMTDTSLTEEQAGPGEPAAPYFITKPVVQKLVEGGSVVFGCQVGGNPKPHVYWKKSGVPLTTGYRYKVSYNKQTGECKLVISMTFADDAGEYTIVVRNKHGETSASASLLEEADYELLMKSQQEMLYQTQVTAFVQEPKVGETAPGFVYSEYEKEYEKEQALIRKKMAKDTVVVRTYVEDQEFHISSFEERLIKEIEYRIIKTTLEELLEEDGEEKMAVDISESEAVESGFDSRIKNYRILEGMGVTFHCKMSGYPLPKIAWYKDGKRIKHGERYQMDFLQDGRASLRIPVVLPEDEGIYTAFASNIKGNAICSGKLYVEPAAPLGAPTYIPTLEPVSRIRSLSPRSVSRSPIRMSPARMSPARMSPARMSPARMSPGRRLEETDESQLERLYKPVFVLKPVSFKCLEGQTARFDLKVVGRPMPETFWFHDGQQIVNDYTHKVVIKEDGTQSLIIVPATPSDSGEWTVVAQNRAGRSSISVILTVEAVEHQVKPMFVEKLKNVNIKEGSRLEMKVRATGNPNPDIVWLKNSDIIVPHKYPKIRIEGTKGEAALKIDSTVSQDSAWYTATAINKAGRDTTRCKVNVEVEFAEPEPERKLIIPRGTYRAKEIAAPELEPLHLRYGQEQWEEGDLYDKEKQQKPFFKKKLTSLRLKRFGPAHFECRLTPIGDPTMVVEWLHDGKPLEAANRLRMINEFGYCSLDYGVAYSRDSGIITCRATNKYGTDHTSATLIVKDEKSLVEESQLPEGRKGLQRIEELERMAHEGALTGVTTDQKEKQKPDIVLYPEPVRVLEGETARFRCRVTGYPQPKVNWYLNGQLIRKSKRFRVRYDGIHYLDIVDCKSYDTGEVKVTAENPEGVIEHKVKLEIQQREDFRSVLRRAPEPRPEFHVHEPGKLQFEVQKVDRPVDTTETKEVVKLKRAERITHEKVPEESEELRSKFKRRTEEGYYEAITAVELKSRKKDESYEELLRKTKDELLHWTKELTEEEKKALAEEGKITIPTFKPDKIELSPSMEAPKIFERIQSQTVGQGSDAHFRVRVVGKPDPECEWYKNGVKIERSDRIYWYWPEDNVCELVIRDVTAEDSASIMVKAINIAGETSSHAFLLVQAKQLITFTQELQDVVAKEKDTMATFECETSEPFVKVKWYKDGMEVHEGDKYRMHSDRKVHFLSILTIDTSDAEDYSCVLVEDENVKTTAKLIVEGAVVEFVKELQDIEVPESYSGELECIVSPENIEGKWYHNDVELKSNGKYTITSRRGRQNLTVKDVTKEDQGEYSFVIDGKKTTCKLKMKPRPIAILQGLSDQKVCEGDIVQLEVKVSLESVEGVWMKDGQEVQPSDRVHIVIDKQSHMLLIEDMTKEDAGNYSFTIPALGLSTSGRVSVYSVDVITPLKDVNVIEGTKAVLECKVSVPDVTSVKWYLNDEQIKPDDRVQAIVKGTKQRLVINRTHASDEGPYKLIVGRVETNCNLSVEKIKIIRGLRDLTCTETQNVVFEVELSHSGIDVLWNFKDKEIKPSSKYKIEAHGKIYKLTVLNMMKDDEGKYTFYAGENMTSGKLTVAGGAISKPLTDQTVAESQEAVFECEVANPDSKGEWLRDGKHLPLTNNIRSESDGHKRRLIIAATKLDDIGEYTYKVATSKTSAKLKVEAVKIKKTLKNLTVTETQDAVFTVELTHPNVKGVQWIKNGVVLESNEKYAISVKGTIYSLRIKNCAIVDESVYGFRLGRLGASARLHVETVKIIKKPKDVTALENATVAFEVSVSHDTVPVKWFHKSVEIKPSDKHRLVSERKVHKLMLQNISPSDAGEYTAVVGQLECKAKLFVETLHITKTMKNIEVPETKTASFECEVSHFNVPSMWLKNGVEIEMSEKFKIVVQGKLHQLIIMNTSTEDSAEYTFVCGNDQVSATLTVTPIMITSMLKDINAEEKDTITFEVTVNYEGISYKWLKNGVEIKSTDKCQMRTKKLTHSLNIRNVHFGDAADYTFVAGKATSTATLYVEARHIEFRKHIKDIKVLEKKRAMFECEVSEPDITVQWMKDDQELQITDRIKIQKEKYVHRLLIPSTRMSDAGKYTVVAGGNVSTAKLFVEGRDVRIRSIKKEVQVIEKQRAVVEFEVNEDDVDAHWYKDGIEINFQVQERHKYVVERRIHRMFISETRQSDAGEYTFVAGRNRSSVTLYVNAPEPPQVLQELQPVTVQSGKPARFCAVISGRPQPKISWYKEEQLLSTGFKCKFLHDGQEYTLLLIEAFPEDAAVYTCEAKNDYGVATTSASLSVEVPEVVSPDQEMPVYPPAIITPLQDTVTSEGQPARFQCRVSGTDLKVSWYSKDKKIKPSRFFRMTQFEDTYQLEIAEAYPEDEGTYTFVASNAVGQVSSTANLSLEAPESILHERIEQEIEMEMKELFSEGESEHSERDTRDAFSDSEDIDHKSMAAKRYASRISSTSSWPEYFKPSFTQKLTFKYVLEGEPVVFTCRLIACPTPEMTWFHNNRPIPTGLRRIIKAESDLHHHSSSLEIKRVQDRDSGSYRLLAINSEGSAESTASLLVIQKGQDEKYLEFLKRAERTHENVEALVERGEDRIKVDLRFTGSPFNKKQDVEQKGMMRTIHFKTMSSAKKTDYMYDEEYLESKSDIRGWLNVGESFLDKETKVKLQRLREARKTLMEKKKLSLLDTSSEISSRTLRSEASDKDILFSREDMKIRSMSDLAESYKVDHSAESIVQNPHALSNQMDQNIESEELPTSFQTIVDEEIFQTEIRMSQEALVKESLPKDHLYGEILVNENTQARGQLEEIMANTTIGESSTYITNVCEKEEVYETPENVSQAITPHASESFGTLVNVEESEEIASERIKKDDLRELQLSASTRIDEFKTEQKEENMRFFENSFRKRPQRCPPSFLQEIESQEVYEGDSCNFVCHFQGYPQPIVTWYNNDMPIPRNQNFIIHSLENYSILTLSSVHHQNEGSITCVLFNQYGTVKTTSMLKVKAKQKHDVKAHKVPVFHDYLDEEEELALVFDQAKGAHPSMSQEGQTNLHLLKTNPPVPPSGDTELLSFPVEIQVTAATPIPEQDKESKEVFQTEELEPKAMPQDQVTQSPKHRFVFLSDITNEPPKMLQEMPKHARCREGDSIILECLISGEPQPVVTWFQNGVLLKQNQKFQFEEVNCSHQLYIKDVNSQDSGKYKCVAENNSGAVESVSDLTVEPVTYRENSQFENIGEIYGKYSRDQQLQDQGESVRAHFYDYPAGPFTPWTNVKEYSVRDYFQSLETIEQIDQKEQVRCIPSREKIPRFVHGASRTIKISKPIRAEFIQCQAEGKERHVSEKSKLHQAEGTVYPFVDDFSDVTIKKEIRNNFGKLGRSEKENVQECAQSDYLPNIHSERISDSYNTKDSSAIVYEESLGEEIHYPGKKVKHRIIEFEKLHVEKGVLEKRPTRTSIVNPPQKKIDDKAFSLKQRESRSSNLNANMYQAEKMSPNTESDSSNIAINLKLLSSQTHKEFDAQEREQQEKISLIDKPAISKRAEHESPITFDLKQFHTQIKHTDVKFQELDSGQPEEAYFKIQHPADTENIVFDLKQMYSHIGDPALEFQGQETREQQEIHYKEKIPSPETLQPDTHNISKSVQNNVFASQEISSSQELSNRTMVEKSSIDENSISLEKEVRHVQEQNLDILKTDLSLKSFSEEIYSESCALLPTSSADIEETDLSEKSCPLENGGRSSISHLKKAASEEKPLGVGEMEEECTLEPELAAFPKQDGGTQEYTDATLEDHRGDVQEADTLHRQLSLSQCFPLLMTEEQQNPGEQISTNIHASGEEKCYEEVQVQNEASFSTLEGEMIETSFSQNIPKLDEAHTTEAAESETSLTQYLLAAGKREVPETKDTRDQAKLVQSESITSMEVEEVTFNTVYEYYNQKQESLGRPLSPESDISIGVGSTTSEEISELDQFYTPPSSVEYFESPKSPDLYFNPSDITKQSSIHSGGETVERYSTPLGEVAERYSTPSEGEVGERYSTPPGETLERYSTPPGETLERYSTPPGETLERYSTPPGETLERYSTPPGETLERYSTPPGEALERYSIPTGGPNPTGTFKTYPSKIEREDGTPNEHFYTPTEERGSAYEIWRSDSFGTPNEAIEPKDNEMPPSFIEPLTKRKVYENTTLGFIVEVEGLPVPGVKWYRNKSLLEPDERIKMERVGNVCSLEISNIQKGEGGEYMCHAVNIIGEAKSFANVDIMPQEERVVALPPPVTHQHVMEFDLEHTTSSRTPSPQEIVLEVELSEKDVKEFEKQVKIVTVPEFTPDHKSMIVSLDVLPFNFVDPNMDSREGEDKELKIDLEVFEMPPRFIMPICDFKIPENSDAVFKCSVIGIPTPEVKWYKEYMCIEPDNIKYVISEEKGSHTLKIRNVCLSDSATYRCRAVNCVGEAICRGFLTMGDSEIFAVIAKKSKVTLSSLMEELVLKSNYTDSFFEFQVVEGPPRFIKGISDCYAPIGTAAYFQCLVRGSPRPTVYWYKDGKLVQGRRFTVEESGTGFHNLFITSLVKSDEGEYRCVATNKSGMAESFAALTLT。L为第5490位亮氨酸(Leu,L)。

p.Leu5490Ter表示：第5490位的亮氨酸(Asp,D)突变为终止密码子。

(2)图1为实施例1的家系图；图2为实施例1中先证者的Sanger测序图；图3为实施例1家系中先证者母亲的Sanger测序图。

如图1-图3所示，先证者携带的突变的TTN基因遗传自先证者父亲；先证者的一个姐姐和先证者哥哥也携带了突变的TTN基因。

实施例2-肥厚型心肌病检测试剂盒

本实施例提供用于检测人类TTN基因c.16469T>G杂合错义变异的试剂盒，包括2×Taq MasterMix(Dye)、能够检测突变的TTN基因的引物等，试剂盒的具体组成如下表2所示。

利用本试剂盒筛选具有c.16469T>G TTN基因突变的患者的具体步骤为：按照实施例1的步骤提取待测者DNA，然后使用经设计的引物组合(SEQ ID NO:5和SEQ ID NO:6)对TTN基因进行扩增，得到PCR产物，最后对PCR产物进行测序。从NCBI(https://www.ncbi.nlm.nih.gov/)数据库获得参考序列和测序结果进行比对，判断待测者TTN基因是否携带c.16469T>G杂合错义变异，协助临床确诊待测者是否患有具有c.16469T>G TTN基因突变的患者。

表2试剂盒组成

实施例3针对家系外的正常人的突变验证

参照实施例1的方法或采用实施例2的肥厚型心肌病检测试剂盒，对370例同种族无关正常人(即家系外正常人)进行TTN基因c.16469T>G突变位点检测，结果均未能检测到该突变。

结果显示，基于TTN基因的c.16469T>G杂合错义变异会导致TTN基因编码的蛋白质发生p.Ter173Gly的改变，而TTN基因是已知致病基因，从而再次证明了TTN基因的c.16469T>G杂合错义变异为致病突变。

以上详细描述了本发明的较佳具体实施例。应当理解，本领域的普通技术人员无需创造性劳动就可以根据本发明的构思作出诸多修改和变化。因此，凡本技术领域中技术人员依本发明的构思在现有技术的基础上通过逻辑分析、推理或者有限的实验可以得到的技术方案，皆应在由权利要求书所确定的保护范围内。

序列表

<110> 百世诺（北京）医学检验实验室有限公司

<120> 突变的TTN基因及肥厚型心肌病检测试剂盒

<160> 6

<170> SIPOSequenceListing 1.0

<210> 1

<211> 50

<212> DNA

<213> homo sapiens

<400> 1

tttaagcagt ttaatggaag aattggtctt aaagagcaac tacacagaca 50

<210> 2

<211> 50

<212> DNA

<213> homo sapiens

<400> 2

tttaagcagt tgaatggaag aattggtctt aaagagcaac tacacagaca 50

<210> 3

<211> 16815

<212> DNA

<213> homo sapiens

<400> 3

atgacaactc aagcaccgac gtttacgcag ccgttacaaa gcgttgtggt actggagggt 60

agtaccgcaa cctttgaggc tcacattagt ggttttccag ttcctgaggt gagctggttt 120

agggatggcc aggtgatttc cacttccact ctgcccggcg tgcagatctc ctttagcgat 180

ggccgcgcta aactgacgat ccccgccgtg actaaagcca acagtggacg atattccctg 240

aaagccacca atggatctgg acaagcgact agtactgctg agcttctcgt gaaagctgag 300

acagcaccac ccaacttcgt tcaacgactg cagagcatga ccgtgagaca aggaagccaa 360

gtgagactcc aagtgagagt gactggaatc cctacacctg tggtgaagtt ctaccgggat 420

ggagccgaaa tccagagctc ccttgatttc caaatttcac aagaaggcga cctctacagc 480

ttactgattg cagaagcata ccctgaggac tcagggacct attcagtaaa tgccaccaat 540

agcgttggaa gagctacttc gactgctgaa ttactggttc aaggtgaaga agaagtacct 600

gctaaaaaga caaagacaat tgtttcgact gctcagatct cagaatcaag acaaacccga 660

attgaaaaga agattgaagc ccactttgat gccagatcaa ttgcaacagt tgagatggtc 720

atagatggtg ccgctgggca acagctgcca cataaaacac ctcccaggat tcctccgaag 780

ccaaagtcaa gatccccaac accaccgtct attgctgcca aagcacagct ggctcggcag 840

cagtccccat cgcccataag acactcccct tccccggtca gacacgtgcg ggcaccgacc 900

ccatctccgg tcaggtccgt gtctccagca gcaagaatct ccacatcccc catcaggtct 960

gttaggtctc cattgctcat gcgtaagact caggcatcca ccgtggccac aggtcctgaa 1020

gtgcctcccc cttggaagca agagggctac gtggcctcct catctgaggc tgagatgaga 1080

gagacaacgc tgacaacctc tactcagatc aggacagaag agagatggga agggagatac 1140

ggtgtccagg agcaagtgac catcagtggt gctgcgggtg ctgccgccag tgtgtcggcc 1200

agtgctagct acgcagcaga ggctgttgcc actggtgcta aagaggtgaa acaagatgct 1260

gacaaaagtg cagctgttgc gactgttgtt gctgccgttg atatggccag agtgagagaa 1320

ccagtgatca gcgctgtaga gcagactgct cagaggacaa ccacgactgc tgtgcacatc 1380

caacctgctc aagaacaggt aagaaaggaa gcggagaaga ctgctgtaac taaggtagta 1440

gtggccgccg ataaagccaa ggaacaagaa ttaaaatcaa gaaccaaaga agtaattacc 1500

acaaagcaag agcagatgca cgtaactcat gagcagataa gaaaagaaac tgaaaaaaca 1560

tttgtaccaa aggtagtaat ttccgcagct aaagccaaag aacaagaaac tagaatttct 1620

gaagaaatta ctaagaaaca gaaacaagta actcaagaag caataagaca ggaaactgag 1680

ataactgctg catccatggt ggtagttgcc actgcaaagt ccacaaaact agaaacagtc 1740

ccgggagctc aagaagaaac taccacacaa caagatcaaa tgcacctaag ttatgaaaag 1800

ataatgaagg aaactaggaa aacagttgta cctaaagtca tagttgccac acccaaagtc 1860

aaagaacaag atttagtatc aagaggtaga gaaggcatta ctaccaaaag agaacaagtg 1920

caaataactc aggagaagat gagaaaggaa gccgagaaaa ctgccttgtc tacaatagca 1980

gttgctactg ctaaagccaa agaacaagaa acaatactga gaactagaga aactatggct 2040

actagacaag aacaaatcca agttacccat ggaaaggtgg acgttggaaa aaaggctgaa 2100

gctgtagcaa cagttgttgc tgcagtagac caggcccgag tcagagagcc cagagagcct 2160

gggcatcttg aagaatccta tgctcagcag accactttgg agtacggata taaggaacgc 2220

atttccgccg caaaggtagc tgagcctccc caacgtccag cctcagaacc ccacgttgtc 2280

cctaaagcag tcaagcctag agtaatccag gctccttctg agactcatat caaaactact 2340

gatcaaaagg gaatgcacat atcatcacag atcaagaaaa ctacagatct aacaacggaa 2400

agattagtcc atgtggataa acgcccccgc acagctagcc ctcactttac tgtttcaaaa 2460

atttctgttc ctaagacaga acatggatat gaggcatcaa tagccggtag tgctattgcc 2520

acattacaaa aagagttgtc agccacatct tctgctcaga agatcaccaa atcggtgaag 2580

gctcctactg tgaagcccag tgagactaga gtaagggcag agcccacacc cttgccacag 2640

ttccccttcg ctgacacacc agatacttac aagagtgaag ctggcgttga ggtgaaaaag 2700

gaagtagggg tgagcatcac tggcaccacc gtccgtgaag agcgctttga agtactgcac 2760

ggacgcgaag ccaaggtaac agaaacagca agagtaccag cacctgttga aattcctgtt 2820

actccaccaa ctttggtctc gggcttaaaa aatgtgactg tcatagaagg tgaatctgtc 2880

accttggagt gccacatctc tggataccca tccccgacag tgacatggta cagggaagac 2940

taccaaatcg aaagttccat tgacttccag ataaccttcc agagtggaat tgctcgtctt 3000

atgattcgcg aagcatttgc ggaagacagc gggcgattta cttgcagtgc tgtaaatgag 3060

gctggaaccg tcagcacatc ctgctatctg gctgtgcagg tgtcagaaga atttgaaaag 3120

gaaaccacag ccgtgactga gaaatttact acagaagaga aacgctttgt tgagtcaaga 3180

gatgtggtta tgactgatac tagcctcaca gaggaacaag cagggcctgg agaacctgcc 3240

gcgccttact ttattacaaa accagtggtc cagaaactgg tggaaggtgg gagcgtggtg 3300

tttggatgcc aagttggcgg caacccaaag ccccatgtat actggaaaaa atctggtgtt 3360

cctctaacca ctggatacag atacaaagtg agttacaaca aacaaaccgg tgaatgcaag 3420

ctggtgattt ctatgacttt tgctgatgat gctggagaat acactattgt tgttcgcaat 3480

aagcatggag aaacttctgc atctgcttcc ttgcttgaag aagctgatta tgagttactg 3540

atgaagtccc agcaagaaat gctttatcag acacaagtga ctgcatttgt tcaagaacct 3600

aaagttggag aaacagcacc tggatttgta tactctgagt atgaaaaaga gtatgaaaaa 3660

gaacaagcct taattaggaa gaaaatggcc aaagatactg tagtggtcag aacttatgta 3720

gaagatcagg aattccatat ttcttccttt gaagagagac ttattaaaga aattgaatat 3780

agaataataa agactacatt agaagaactt cttgaagaag atggagaaga aaagatggca 3840

gttgacattt ctgaatctga agctgttgaa tcaggatttg attcaagaat caagaattat 3900

agaattcttg aggggatggg tgtcactttt cattgcaaga tgtctggata tccattacca 3960

aagattgctt ggtacaaaga tggcaagcgc atcaaacatg gagaaagata ccaaatggac 4020

tttctacaag atggcagagc tagtctgcgt atacctgttg ttcttccaga agatgaagga 4080

atctacactg catttgccag caatattaaa ggaaatgcaa tttgctcagg gaaattgtat 4140

gtggagcctg ctgcaccact tggagctccg acttacattc ccacactaga gccagtgagc 4200

agaatcagat ctctctctcc acgttcagtg agcaggtctc ctatacgcat gtctcctgca 4260

cggatgtcac ctgcaaggat gtctcctgca cggatgtccc ctgcaagaat gtcccctgga 4320

cgtaggctgg aggagacaga tgagtcacaa cttgagagac tatataaacc agtctttgtg 4380

ttaaaacctg tttctttcaa atgtttagaa gggcaaactg ccagatttga cttaaaggtt 4440

gttggtagac ctatgccaga gacgttctgg tttcatgatg gccagcaaat tgtcaatgac 4500

tatacccata aagtagtcat taaagaagat ggtactcaat cactaattat tgtccctgcc 4560

acacccagtg attctgggga atggactgtg gttgcccaaa acagggcagg cagatcttca 4620

atttcagtga ttttaactgt ggaagctgtg gaacatcagg taaaaccgat gtttgtagaa 4680

aaactgaaaa atgtcaatat aaaggaaggt tcccgacttg aaatgaaagt cagagctacg 4740

ggtaacccca accctgacat tgtatggttg aaaaacagtg acatcattgt gcctcataaa 4800

tatcccaaaa tcagaattga aggaaccaag ggagaagctg cccttaaaat cgattccact 4860

gtcagccaag attctgcctg gtatactgcg actgctatta ataaagctgg cagagacact 4920

acaagatgca aagtaaatgt tgaagttgag tttgcagagc ctgagccaga gagaaagtta 4980

atcatcccac gggggacata tagagcaaag gagattgcag ccccagaact ggagcccctc 5040

catttgcgat atggccaaga gcaatgggaa gaaggtgatc tctatgacaa agagaaacaa 5100

cagaaaccat ttttcaagaa aaaactcact tccttaagac ttaagcgctt tgggcctgcc 5160

cactttgaat gcaggctaac acccattggt gacccaacga tggtggtgga gtggctccat 5220

gatggaaagc cacttgaagc agccaacagg ctccgtatga tcaatgaatt tgggtactgc 5280

agccttgatt atggcgttgc atattctaga gacagtggta tcattacttg cagagccact 5340

aacaaatatg gaacagatca cacatctgct acccttattg ttaaagatga gaaaagtctt 5400

gtggaagaat cccaattgcc tgaggggagg aaaggcttac agagaattga agaattagag 5460

agaatggctc atgaaggtgc acttacaggt gtaacaacag atcagaaaga aaagcaaaag 5520

ccagacattg tcttgtaccc agagccagtt agagtacttg aaggggagac tgcaaggttc 5580

cgctgcaggg taacaggcta ccctcagccc aaagtcaact ggtacctcaa tggacagctc 5640

atccgcaaaa gcaaaaggtt cagagttcgc tatgatggta tccattacct ggacatcgtg 5700

gactgcaaat catatgacac aggtgaagtg aaggtcaccg cggaaaatcc tgaaggtgtg 5760

atagagcata aagtgaagct tgagattcaa cagagggaag attttaggtc tgtccttagg 5820

agagctcctg aaccaaggcc tgagtttcac gtacatgaac caggaaagct tcagtttgaa 5880

gtacaaaaag tggatagacc tgttgacacc actgaaacca aagaagttgt gaagttgaaa 5940

agggctgaaa gaattaccca tgaaaaagtg cctgaagagt cggaagagct gcgcagtaaa 6000

ttcaagcgca gaacagaaga gggctattat gaagccatta ccgctgtgga gctcaagtct 6060

cgaaagaagg atgaatccta tgaggaactc ctcaggaaga caaaagatga acttctccac 6120

tggaccaaag agttaactga agaggaaaag aaagctcttg ccgaagaagg caaaatcacg 6180

attccaactt ttaaacctga caagattgaa ctaagtccta gtatggaggc tccaaaaatc 6240

ttcgaaagaa tccagagcca aacagtgggc caaggatctg atgcacactt ccgggtcaga 6300

gtcgtgggga aaccagaccc cgaatgtgaa tggtacaaaa atggtgtcaa aattgaacgg 6360

tctgaccgga tctactggta ctggcccgaa gacaatgttt gtgaattggt cataagagat 6420

gtgactgctg aggactctgc cagcatcatg gtaaaagcca tcaacatagc tggagaaacc 6480

tccagtcacg cattcttact tgtccaagcc aagcaattga tcactttcac acaggaatta 6540

caagatgttg ttgctaagga aaaagacact atggcaacct ttgaatgtga aacttcagaa 6600

ccatttgtca aagtgaaatg gtataaagat ggtatggagg ttcatgaggg agataaatac 6660

aggatgcact ctgacagaaa ggttcacttc ctctccatac tgaccattga tacgtctgat 6720

gctgaagatt acagctgtgt acttgtggaa gatgaaaatg tcaaaacgac tgctaaactt 6780

attgttgaag gtgcagttgt tgagtttgtg aaagaacttc aggacataga agttccagaa 6840

tcatattcag gagaattaga gtgcattgta tccccagaaa atatagaagg aaaatggtat 6900

cataatgatg tggagcttaa atccaatggc aaatatacaa ttacatctcg tcgtggacgt 6960

cagaacctca cggtcaagga tgtaaccaag gaggaccagg gagaatacag ctttgtcatc 7020

gacgggaaaa agacaacctg taaattaaag atgaaacccc gccccattgc tatcctacaa 7080

ggacttagtg accaaaaagt ctgtgagggt gacattgttc agcttgaagt taaagtctcc 7140

ttggaaagtg tggaaggcgt ctggatgaaa gacggccaag aagtgcagcc cagtgacagg 7200

gttcacattg tgatagacaa acaatctcat atgctgctca ttgaagacat gactaaggaa 7260

gatgctggaa attactcttt caccattcca gcccttggcc tctccaccag tgggcgtgtc 7320

tctgtctata gtgtggacgt gataacacct ctaaaagatg ttaatgtgat tgaaggcacc 7380

aaggctgtgc ttgaatgtaa ggtgtcagtc cctgatgtga cttctgttaa gtggtactta 7440

aatgatgaac aaatcaagcc tgatgaccgt gtacaggcca ttgtgaaagg tactaaacag 7500

cgactagtca ttaaccgaac tcatgcttca gacgaaggac cttacaagct gatagttggc 7560

agagttgaaa ccaactgtaa tctctctgta gaaaaaatta aaattatcag aggtcttcgt 7620

gaccttacct gtacagaaac tcaaaatgtg gtgtttgagg ttgagctgtc ccactctgga 7680

attgatgtcc tgtggaattt taaggacaag gaaatcaagc ccagttctaa atataaaatt 7740

gaagcacatg gaaaaatata taaattgaca gttctaaata tgatgaaaga tgatgaagga 7800

aaatacacat tttacgcggg agaaaatatg acatctggaa aacttactgt ggcaggtggg 7860

gccatctcca agccactcac agatcagacc gtagctgaat cccaggaagc tgtgtttgaa 7920

tgtgaagttg ccaacccaga ttccaaaggc gaatggttga gggatggcaa acacctacca 7980

ctgactaaca acatcagaag tgagtctgat ggccacaaaa ggagacttat cattgctgcc 8040

accaaattag atgacattgg agaatatacc tacaaggtgg ccacctccaa aacatctgcc 8100

aaactcaaag ttgaagctgt caaaattaag aagactctga agaacctcac agtgacagaa 8160

acacaggatg ctgttttcac tgtcgagctt acacacccta atgtcaaagg tgtccagtgg 8220

atcaaaaatg gagttgtgct ggaatccaat gaaaagtatg ctatctctgt caaaggaaca 8280

atttactctc tgaggattaa aaactgtgcc atcgtggatg agtctgttta tggcttcagg 8340

cttggaaggc ttggagccag tgccagactg cacgtggaga ctgtcaagat cattaaaaag 8400

ccaaaggatg tgacagcctt ggaaaatgcc actgttgcct ttgaagttag tgtttcccat 8460

gacactgttc cagtaaaatg gttccataag agtgtggaaa ttaagccaag tgacaaacac 8520

agactggtct cagaaaggaa agtccacaag ctgatgctgc agaacatctc cccctcagat 8580

gctggggaat acacagctgt ggtcgggcaa ttggaatgca aagcaaaact gtttgtggag 8640

acattacata ttacaaaaac catgaaaaat atcgaggtgc ctgagaccaa aactgcctct 8700

tttgagtgtg aggtgtccca cttcaatgtc ccttccatgt ggctgaagaa tggtgtggaa 8760

attgagatga gtgaaaagtt caagatagtt gtgcagggaa aactccatca gctgatcatc 8820

atgaacacca gcacagagga ctcggcagaa tacacatttg tctgtggcaa tgaccaagtc 8880

agtgccaccc tgacagtcac cccaatcatg attacttcca tgctgaaaga catcaacgct 8940

gaagaaaaag acactattac ttttgaggtg acagtgaact atgaaggcat ctcttacaaa 9000

tggttaaaga atggtgtgga aatcaaatca actgacaagt gccagatgag aaccaaaaag 9060

ctcacacact cactgaacat caggaatgtt cactttgggg atgctgctga ctacaccttt 9120

gtggctggaa aagcaacatc aacagccaca ctttatgtgg aagctcgtca tatagaattt 9180

aggaaacaca ttaaggacat taaggtactg gagaagaagc gagccatgtt tgaatgtgaa 9240

gtttctgaac ctgacatcac tgtacagtgg atgaaagatg accaggaact gcagatcaca 9300

gacagaataa agattcagaa ggagaaatat gtccaccgcc ttctgatccc atccacccgg 9360

atgtctgatg ctgggaagta cacagtggtg gcaggaggca acgtgtcaac tgcaaaactc 9420

tttgtagaag gcagagatgt tcgcatccga agtattaaaa aggaggttca ggtcattgag 9480

aaacagcgtg ctgttgttga atttgaggtc aatgaagacg atgttgatgc ccactggtat 9540

aaagatggca ttgaaatcaa tttccaagtt caagaacgac acaaatatgt agtggaaaga 9600

agaatccacc gaatgtttat ctctgagacc agacagagcg atgcaggaga atacaccttt 9660

gtggcaggaa ggaacaggag ttctgtcact ctctatgtca atgctcctga accgccccaa 9720

gttctgcagg agctccagcc tgtcactgtg cagtctggca agcctgcccg cttctgtgcc 9780

gtgatatccg gaagaccaca gcccaaaatt tcctggtaca aggaagagca gctgctttcc 9840

actggcttca agtgcaaatt tcttcatgat gggcaagaat acacgctttt gctaattgaa 9900

gccttcccag aggatgcggc agtctatacc tgtgaagcca agaatgacta tggtgttgcc 9960

acaacatcag cttcactctc agtggaagtt ccagaagttg tgtctcctga tcaggaaatg 10020

cctgtttatc cacctgccat catcaccccg cttcaggaca ctgtcacttc tgaagggcag 10080

ccagcccgtt ttcaatgccg ggtttctgga acagatctaa aagtgtcgtg gtacagcaaa 10140

gacaagaaaa tcaagccatc tcggttcttt agaatgactc aatttgaaga cacttatcaa 10200

ctggaaattg ccgaagctta tccagaagat gaaggaactt acacgtttgt tgctagtaat 10260

gctgtaggcc aagtatcaag cacagccaac ctgagtctgg aagctcctga atcaattttg 10320

catgagagga ttgaacaaga gattgagatg gaaatgaaag aattattctc tgagggggaa 10380

tctgaacatt cagaaaggga tacacgtgac gccttttcag attctgaaga catagaccac 10440

aaatccatgg ctgctaaaag atatgcaagt agaatatcat ctacaagctc ctggcctgaa 10500

tattttaagc cttcttttac ccagaaactt acatttaaat atgttttaga gggtgaaccg 10560

gttgttttta catgtagatt aattgcctgt ccaactccag aaatgacttg gtttcataac 10620

aatcggccca tcccaacagg tcttcgtcgg attataaaag ctgagagtga tttacaccat 10680

cactcttcca gcttagagat taaaagggtc caagacagag attctggaag ttataggtta 10740

ctagcaatta atagtgaagg gtctgcagaa tcaactgcat cattgcttgt tatccaaaaa 10800

gggcaagatg agaaatattt agaatttctg aaaagagcag aacggacaca tgaaaatgtg 10860

gaggctttag ttgaaagggg agaagatagg ataaaggttg acctgaggtt tactggctct 10920

ccctttaaca aaaaacaaga tgtggaacaa aagggaatga tgagaactat acattttaag 10980

acaatgagtt ctgccaagaa aacagattac atgtatgatg aagaatattt agaaagtaaa 11040

tctgacataa gaggttggct taatgtaggt gaaagtttcc tggacaagga gaccaaagtg 11100

aagttgcaac gtttaaggga ggctagaaaa acattaatgg agaaaaagaa attatctctt 11160

ttagatacgt cttctgaaat aagctcaaga actttgagaa gtgaagctag tgataaagat 11220

attctgttct ctagagagga catgaaaatc agatctatgt ctgatctagc tgaaagttat 11280

aaggtagatc attcagctga gagtattgtg caaaatccac atgccctttc taatcaaatg 11340

gatcaaaata tagaatctga ggaacttccc acaagctttc aaactattgt tgatgaagaa 11400

attttccaga ctgaaataag aatgagccaa gaagcactgg taaaggaaag tctaccaaaa 11460

gaccatttat atggtgaaat tctagtaaat gaaaataccc aagcaagagg acagctggaa 11520

gaaattatgg ccaatactac aattggagag tcatccacat atatcactaa tgtatgtgag 11580

aaggaggaag tatatgagac tcctgaaaat gtgtctcaag ctattacacc acatgccagc 11640

gaatcttttg gtacacttgt aaatgttgaa gaaagtgaag aaatagctag tgaaagaata 11700

aaaaaggatg atttgagaga attacaactc tctgcttcta cacgaattga tgaattcaaa 11760

accgaacaga aggaagaaaa catgagattt tttgaaaatt cttttcgaaa acgcccacaa 11820

cgttgcccac cttcatttct tcaagaaatt gaatctcaag aagtttatga aggtgacagt 11880

tgtaattttg tgtgtcattt tcaaggatat cctcaaccta tagtgacgtg gtataacaat 11940

gacatgccaa tcccacgtaa tcaaaacttt atcattcatt cgttggaaaa ctattcaata 12000

ttaactcttt catctgttca tcatcagaat gaaggttcta ttacttgtgt gctatttaac 12060

caatatggaa cagtaaaaac aaccagtatg cttaaagtga aagcaaaaca aaaacatgat 12120

gtcaaagcac ataaagtccc agtgttccat gactacttgg atgaggaaga agagttagca 12180

ttggtgtttg accaagcaaa aggcgcccat ccatctatga gtcaagaggg ccaaacaaat 12240

cttcatttgt taaaaactaa cccaccagtt cctccctctg gagacacaga attgctttcc 12300

tttcctgtag aaattcaggt aacagcagct actcctatcc cagaacagga taaagagtct 12360

aaagaagtgt ttcaaactga ggagctggaa cctaaagcaa tgcctcaaga tcaagttact 12420

caatcaccaa aacacagatt tgtatttttg tctgatatta ctaatgaacc accaaaaatg 12480

ttacaagaaa tgccaaagca tgccaggtgt agagaagggg attccatcat tcttgaatgt 12540

ttaatatctg gtgagcccca gccagttgta acatggtttc aaaatggagt ccttttaaag 12600

cagaaccaga agtttcagtt tgaagaagtt aattgtagcc accaattata tattaaggat 12660

gttaattctc aagattctgg aaaatataaa tgtgttgctg aaaacaattc aggggcagtt 12720

gaaagtgttt cagatctaac agtggagcct gtcacttata gagaaaatag tcaattcgaa 12780

aatattggtg aaatttatgg aaaatattcc agagatcagc aactgcaaga ccagggagaa 12840

tctgtaaggg cacattttta tgattatcca gctggtccct ttactccctg gacaaatgta 12900

aaagaatatt cagtaaggga ctattttcaa agccttgaga ctattgagca aatagaccag 12960

aaagagcagg tgcgttgcat accttctaga gaaaaaattc ccagatttgt gcatggtgct 13020

tcaagaacca taaaaatcag caagcccatc agggctgaat tcatacaatg tcaggctgaa 13080

gggaaagaga gacatgtaag tgaaaaatca aagctgcacc aagcagaggg tactgtttat 13140

ccatttgttg atgatttcag tgatgtcact attaagaaag aaataagaaa taattttgga 13200

aaacttggta gatcagaaaa ggaaaatgta caagaatgtg cccaaagtga ctatttacca 13260

aatattcact ctgagagaat ttctgacagt tacaatacaa aagattcatc tgccattgta 13320

tatgaagaat cccttggtga agagatacac tacccgggga aaaaggtgaa gcatagaatt 13380

atcgaatttg aaaaattaca tgtagaaaaa ggagttctag aaaaaagacc taccagaaca 13440

tcaattgtta atcctcctca aaagaagatt gatgacaaag ccttttcatt aaagcaaaga 13500

gaatcaagat caagcaatct aaatgcaaat atgtatcagg cagagaaaat gtctccaaat 13560

actgaatcag attcatctaa cattgcaata aatttaaagc tgctttcctc tcaaactcat 13620

aaagaatttg acgcacaaga aagggaacaa caggaaaaaa taagtcttat agataaacct 13680

gcaatttcta aaagagctga acatgaatca cctattacat ttgacttaaa gcagtttcac 13740

actcaaataa aacacacaga tgtgaaattc caagaattag atagtggtca accagaagaa 13800

gcttatttta aaatccaaca tcctgctgac actgagaaca ttgtatttga tctaaaacaa 13860

atgtattctc atataggaga tccagctctg gagttccaag ggcaagaaac tagggaacag 13920

caggaaatac attataaaga aaaaattcct agccctgaaa cgttacaacc tgacacacac 13980

aatatctcta aaagtgtgca aaataatgta tttgccagtc aagaaatttc ttccagtcaa 14040

gagctttcaa atagaactat ggtggagaaa agtagtattg atgaaaattc catttcttta 14100

gaaaaagaag tccgacatgt acaggaacaa aacttagaca ttttaaaaac tgatctttct 14160

cttaaatcct tttctgaaga aatctatagt gaatcatgtg ccctacttcc aacctcatct 14220

gcagatatag aagaaactga tctttctgag aaaagttgtc ctctagaaaa tggaggcaga 14280

agttccatct cacatttgaa aaaagcagca agtgaggaaa agcctttagg ggttggtgaa 14340

atggaagaag aatgcactct agaaccagag ttggcagcat ttccaaagca ggatggtggg 14400

acacaggaat atacagatgc cactttggaa gaccacagag gtgatgttca ggaagctgac 14460

acactccata gacagctctc cctgagtcag tgcttcccac tcttgatgac tgaagaacaa 14520

cagaatccag gtgaacaaat aagtacaaac attcatgcct ctggagaaga aaaatgttat 14580

gaagaagttc aagttcagaa tgaagcttct ttctccactt tagaaggaga aatgatagaa 14640

actagttttt ctcaaaatat tcctaaatta gatgaggcac ataccactga ggcagcagaa 14700

tctgagacct ccctaacaca atatttactt gctgctggaa agcgtgaggt tcctgaaact 14760

aaagacacca gagaccaggc aaagcttgtc cagagtgaat caatcacttc aatggaggtg 14820

gaagaagtaa ctttcaacac tgtgtatgaa tactacaacc agaaacagga atcactaggt 14880

cgtccacttt ctcctgagtc tgacatttcc attggtgtgg gaagtacaac cagtgaagaa 14940

atatctgagt tagatcagtt ttatacccca ccatcatctg ttgaatattt tgaatctcca 15000

aagtcccctg acttatattt taatccttca gatataacta aacaatcctc aatacattca 15060

ggaggtgaga cagttgaaag atattccaca cctttagggg aagttgctga aagatattca 15120

acaccttccg aaggtgaggt aggagaaaga tactccacac ccccagggga gacactagag 15180

agatactcca cacctccagg agagactcta gagagatact ccacaccccc aggagagact 15240

ctagagagat attccacacc cccaggagag actctggaga gatactccac acccccagga 15300

gagactctag agcgatattc cacaccccca ggggaggcac tagagagata ttctattcct 15360

actggaggac caaaccccac tggtactttt aaaacatatc catcaaaaat agaaagggaa 15420

gacggtacac caaatgagca tttctacaca cctacagaag agaggggttc agcttatgaa 15480

atatggcgtt ccgattcatt tggtacaccc aatgaagcca ttgagccaaa agacaatgaa 15540

atgcctccat cttttattga acctctgacc aaaaggaagg tatatgaaaa cacaacacta 15600

ggcttcattg ttgaagttga aggtcttcca gttcctggtg tgaaatggta tcgaaataaa 15660

tctttactag agccagatga aagaatcaaa atggaaagag tgggtaatgt gtgttcactg 15720

gaaatttcta acattcaaaa aggagaaggg ggagagtaca tgtgtcatgc tgtaaacatc 15780

ataggggaag caaagagctt tgcaaatgta gacataatgc cccaggaaga aagagtggtg 15840

gcactaccac ctccagtaac acatcagcat gtcatggagt ttgatttgga acacaccaca 15900

tcatcaagaa caccttctcc tcaagaaatt gtcctggaag ttgaattaag tgaaaaagac 15960

gttaaagaat ttgagaagca ggtgaaaata gtgacagttc ccgaatttac tcctgaccat 16020

aaaagtatga ttgtgagtct agatgttctt ccatttaatt ttgtagatcc aaatatggat 16080

tcaagggagg gagaagacaa agaactaaaa attgatttag aagtatttga aatgcctcct 16140

cgctttataa tgcctatttg tgattttaaa attccagaaa attcagatgc tgtattcaaa 16200

tgttcagtca tagggatccc gactcccgaa gttaagtggt ataaagaata tatgtgtatt 16260

gagccagata atattaaata cgtgattagc gaggagaagg gaagtcacac tcttaaaatt 16320

cgaaatgtct gtctttctga tagtgcaaca tacaggtgca gagctgtgaa ttgtgtagga 16380

gaggctatct gtcggggatt cctcaccatg ggagattctg aaatatttgc tgtgatagca 16440

aagaaaagca aagtgacttt aagcagttta atggaagaat tggtcttaaa gagcaactac 16500

acagacagtt tttttgaatt tcaggtggtg gaagggcctc ccaggtttat caaaggtatt 16560

tctgactgtt atgcaccaat aggtacagca gcatattttc agtgcttagt tcgtggctct 16620

ccaagaccca cggtttactg gtacaaagat ggaaaattag tccaaggaag aaggttcact 16680

gttgaggaaa gtggcacagg gttccataac ctgtttataa caagcttagt aaagagtgat 16740

gaaggagagt ataggtgtgt agctacaaac aaatcaggaa tggctgagag ctttgcagca 16800

ctcaccttaa cttaa 16815

<210> 4

<211> 5604

<212> PRT

<213> homo sapiens

<400> 4

Met Thr Thr Gln Ala Pro Thr Phe Thr Gln Pro Leu Gln Ser Val Val

1 5 10 15

Val Leu Glu Gly Ser Thr Ala Thr Phe Glu Ala His Ile Ser Gly Phe

20 25 30

Pro Val Pro Glu Val Ser Trp Phe Arg Asp Gly Gln Val Ile Ser Thr

35 40 45

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

50 55 60

Leu Thr Ile Pro Ala Val Thr Lys Ala Asn Ser Gly Arg Tyr Ser Leu

65 70 75 80

Lys Ala Thr Asn Gly Ser Gly Gln Ala Thr Ser Thr Ala Glu Leu Leu

85 90 95

Val Lys Ala Glu Thr Ala Pro Pro Asn Phe Val Gln Arg Leu Gln Ser

100 105 110

Met Thr Val Arg Gln Gly Ser Gln Val Arg Leu Gln Val Arg Val Thr

115 120 125

Gly Ile Pro Thr Pro Val Val Lys Phe Tyr Arg Asp Gly Ala Glu Ile

130 135 140

Gln Ser Ser Leu Asp Phe Gln Ile Ser Gln Glu Gly Asp Leu Tyr Ser

145 150 155 160

Leu Leu Ile Ala Glu Ala Tyr Pro Glu Asp Ser Gly Thr Tyr Ser Val

165 170 175

Asn Ala Thr Asn Ser Val Gly Arg Ala Thr Ser Thr Ala Glu Leu Leu

180 185 190

Val Gln Gly Glu Glu Glu Val Pro Ala Lys Lys Thr Lys Thr Ile Val

195 200 205

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

210 215 220

Ile Glu Ala His Phe Asp Ala Arg Ser Ile Ala Thr Val Glu Met Val

225 230 235 240

Ile Asp Gly Ala Ala Gly Gln Gln Leu Pro His Lys Thr Pro Pro Arg

245 250 255

Ile Pro Pro Lys Pro Lys Ser Arg Ser Pro Thr Pro Pro Ser Ile Ala

260 265 270

Ala Lys Ala Gln Leu Ala Arg Gln Gln Ser Pro Ser Pro Ile Arg His

275 280 285

Ser Pro Ser Pro Val Arg His Val Arg Ala Pro Thr Pro Ser Pro Val

290 295 300

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

305 310 315 320

Val Arg Ser Pro Leu Leu Met Arg Lys Thr Gln Ala Ser Thr Val Ala

325 330 335

Thr Gly Pro Glu Val Pro Pro Pro Trp Lys Gln Glu Gly Tyr Val Ala

340 345 350

Ser Ser Ser Glu Ala Glu Met Arg Glu Thr Thr Leu Thr Thr Ser Thr

355 360 365

Gln Ile Arg Thr Glu Glu Arg Trp Glu Gly Arg Tyr Gly Val Gln Glu

370 375 380

Gln Val Thr Ile Ser Gly Ala Ala Gly Ala Ala Ala Ser Val Ser Ala

385 390 395 400

Ser Ala Ser Tyr Ala Ala Glu Ala Val Ala Thr Gly Ala Lys Glu Val

405 410 415

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

420 425 430

Val Asp Met Ala Arg Val Arg Glu Pro Val Ile Ser Ala Val Glu Gln

435 440 445

Thr Ala Gln Arg Thr Thr Thr Thr Ala Val His Ile Gln Pro Ala Gln

450 455 460

Glu Gln Val Arg Lys Glu Ala Glu Lys Thr Ala Val Thr Lys Val Val

465 470 475 480

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

485 490 495

Glu Val Ile Thr Thr Lys Gln Glu Gln Met His Val Thr His Glu Gln

500 505 510

Ile Arg Lys Glu Thr Glu Lys Thr Phe Val Pro Lys Val Val Ile Ser

515 520 525

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

530 535 540

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

545 550 555 560

Ile Thr Ala Ala Ser Met Val Val Val Ala Thr Ala Lys Ser Thr Lys

565 570 575

Leu Glu Thr Val Pro Gly Ala Gln Glu Glu Thr Thr Thr Gln Gln Asp

580 585 590

Gln Met His Leu Ser Tyr Glu Lys Ile Met Lys Glu Thr Arg Lys Thr

595 600 605

Val Val Pro Lys Val Ile Val Ala Thr Pro Lys Val Lys Glu Gln Asp

610 615 620

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

625 630 635 640

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

645 650 655

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

660 665 670

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

675 680 685

Thr His Gly Lys Val Asp Val Gly Lys Lys Ala Glu Ala Val Ala Thr

690 695 700

Val Val Ala Ala Val Asp Gln Ala Arg Val Arg Glu Pro Arg Glu Pro

705 710 715 720

Gly His Leu Glu Glu Ser Tyr Ala Gln Gln Thr Thr Leu Glu Tyr Gly

725 730 735

Tyr Lys Glu Arg Ile Ser Ala Ala Lys Val Ala Glu Pro Pro Gln Arg

740 745 750

Pro Ala Ser Glu Pro His Val Val Pro Lys Ala Val Lys Pro Arg Val

755 760 765

Ile Gln Ala Pro Ser Glu Thr His Ile Lys Thr Thr Asp Gln Lys Gly

770 775 780

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

785 790 795 800

Arg Leu Val His Val Asp Lys Arg Pro Arg Thr Ala Ser Pro His Phe

805 810 815

Thr Val Ser Lys Ile Ser Val Pro Lys Thr Glu His Gly Tyr Glu Ala

820 825 830

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

835 840 845

Thr Ser Ser Ala Gln Lys Ile Thr Lys Ser Val Lys Ala Pro Thr Val

850 855 860

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

865 870 875 880

Phe Pro Phe Ala Asp Thr Pro Asp Thr Tyr Lys Ser Glu Ala Gly Val

885 890 895

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

900 905 910

Glu Glu Arg Phe Glu Val Leu His Gly Arg Glu Ala Lys Val Thr Glu

915 920 925

Thr Ala Arg Val Pro Ala Pro Val Glu Ile Pro Val Thr Pro Pro Thr

930 935 940

Leu Val Ser Gly Leu Lys Asn Val Thr Val Ile Glu Gly Glu Ser Val

945 950 955 960

Thr Leu Glu Cys His Ile Ser Gly Tyr Pro Ser Pro Thr Val Thr Trp

965 970 975

Tyr Arg Glu Asp Tyr Gln Ile Glu Ser Ser Ile Asp Phe Gln Ile Thr

980 985 990

Phe Gln Ser Gly Ile Ala Arg Leu Met Ile Arg Glu Ala Phe Ala Glu

995 1000 1005

Asp Ser Gly Arg Phe Thr Cys Ser Ala Val Asn Glu Ala Gly Thr Val

1010 1015 1020

Ser Thr Ser Cys Tyr Leu Ala Val Gln Val Ser Glu Glu Phe Glu Lys

1025 1030 1035 1040

Glu Thr Thr Ala Val Thr Glu Lys Phe Thr Thr Glu Glu Lys Arg Phe

1045 1050 1055

Val Glu Ser Arg Asp Val Val Met Thr Asp Thr Ser Leu Thr Glu Glu

1060 1065 1070

Gln Ala Gly Pro Gly Glu Pro Ala Ala Pro Tyr Phe Ile Thr Lys Pro

1075 1080 1085

Val Val Gln Lys Leu Val Glu Gly Gly Ser Val Val Phe Gly Cys Gln

1090 1095 1100

Val Gly Gly Asn Pro Lys Pro His Val Tyr Trp Lys Lys Ser Gly Val

1105 1110 1115 1120

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

1125 1130 1135

Gly Glu Cys Lys Leu Val Ile Ser Met Thr Phe Ala Asp Asp Ala Gly

1140 1145 1150

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

1155 1160 1165

Ala Ser Leu Leu Glu Glu Ala Asp Tyr Glu Leu Leu Met Lys Ser Gln

1170 1175 1180

Gln Glu Met Leu Tyr Gln Thr Gln Val Thr Ala Phe Val Gln Glu Pro

1185 1190 1195 1200

Lys Val Gly Glu Thr Ala Pro Gly Phe Val Tyr Ser Glu Tyr Glu Lys

1205 1210 1215

Glu Tyr Glu Lys Glu Gln Ala Leu Ile Arg Lys Lys Met Ala Lys Asp

1220 1225 1230

Thr Val Val Val Arg Thr Tyr Val Glu Asp Gln Glu Phe His Ile Ser

1235 1240 1245

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

1250 1255 1260

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

1265 1270 1275 1280

Val Asp Ile Ser Glu Ser Glu Ala Val Glu Ser Gly Phe Asp Ser Arg

1285 1290 1295

Ile Lys Asn Tyr Arg Ile Leu Glu Gly Met Gly Val Thr Phe His Cys

1300 1305 1310

Lys Met Ser Gly Tyr Pro Leu Pro Lys Ile Ala Trp Tyr Lys Asp Gly

1315 1320 1325

Lys Arg Ile Lys His Gly Glu Arg Tyr Gln Met Asp Phe Leu Gln Asp

1330 1335 1340

Gly Arg Ala Ser Leu Arg Ile Pro Val Val Leu Pro Glu Asp Glu Gly

1345 1350 1355 1360

Ile Tyr Thr Ala Phe Ala Ser Asn Ile Lys Gly Asn Ala Ile Cys Ser

1365 1370 1375

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

1380 1385 1390

Ile Pro Thr Leu Glu Pro Val Ser Arg Ile Arg Ser Leu Ser Pro Arg

1395 1400 1405

Ser Val Ser Arg Ser Pro Ile Arg Met Ser Pro Ala Arg Met Ser Pro

1410 1415 1420

Ala Arg Met Ser Pro Ala Arg Met Ser Pro Ala Arg Met Ser Pro Gly

1425 1430 1435 1440

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

1445 1450 1455

Pro Val Phe Val Leu Lys Pro Val Ser Phe Lys Cys Leu Glu Gly Gln

1460 1465 1470

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

1475 1480 1485

Phe Trp Phe His Asp Gly Gln Gln Ile Val Asn Asp Tyr Thr His Lys

1490 1495 1500

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

1505 1510 1515 1520

Thr Pro Ser Asp Ser Gly Glu Trp Thr Val Val Ala Gln Asn Arg Ala

1525 1530 1535

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

1540 1545 1550

Gln Val Lys Pro Met Phe Val Glu Lys Leu Lys Asn Val Asn Ile Lys

1555 1560 1565

Glu Gly Ser Arg Leu Glu Met Lys Val Arg Ala Thr Gly Asn Pro Asn

1570 1575 1580

Pro Asp Ile Val Trp Leu Lys Asn Ser Asp Ile Ile Val Pro His Lys

1585 1590 1595 1600

Tyr Pro Lys Ile Arg Ile Glu Gly Thr Lys Gly Glu Ala Ala Leu Lys

1605 1610 1615

Ile Asp Ser Thr Val Ser Gln Asp Ser Ala Trp Tyr Thr Ala Thr Ala

1620 1625 1630

Ile Asn Lys Ala Gly Arg Asp Thr Thr Arg Cys Lys Val Asn Val Glu

1635 1640 1645

Val Glu Phe Ala Glu Pro Glu Pro Glu Arg Lys Leu Ile Ile Pro Arg

1650 1655 1660

Gly Thr Tyr Arg Ala Lys Glu Ile Ala Ala Pro Glu Leu Glu Pro Leu

1665 1670 1675 1680

His Leu Arg Tyr Gly Gln Glu Gln Trp Glu Glu Gly Asp Leu Tyr Asp

1685 1690 1695

Lys Glu Lys Gln Gln Lys Pro Phe Phe Lys Lys Lys Leu Thr Ser Leu

1700 1705 1710

Arg Leu Lys Arg Phe Gly Pro Ala His Phe Glu Cys Arg Leu Thr Pro

1715 1720 1725

Ile Gly Asp Pro Thr Met Val Val Glu Trp Leu His Asp Gly Lys Pro

1730 1735 1740

Leu Glu Ala Ala Asn Arg Leu Arg Met Ile Asn Glu Phe Gly Tyr Cys

1745 1750 1755 1760

Ser Leu Asp Tyr Gly Val Ala Tyr Ser Arg Asp Ser Gly Ile Ile Thr

1765 1770 1775

Cys Arg Ala Thr Asn Lys Tyr Gly Thr Asp His Thr Ser Ala Thr Leu

1780 1785 1790

Ile Val Lys Asp Glu Lys Ser Leu Val Glu Glu Ser Gln Leu Pro Glu

1795 1800 1805

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

1810 1815 1820

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

1825 1830 1835 1840

Pro Asp Ile Val Leu Tyr Pro Glu Pro Val Arg Val Leu Glu Gly Glu

1845 1850 1855

Thr Ala Arg Phe Arg Cys Arg Val Thr Gly Tyr Pro Gln Pro Lys Val

1860 1865 1870

Asn Trp Tyr Leu Asn Gly Gln Leu Ile Arg Lys Ser Lys Arg Phe Arg

1875 1880 1885

Val Arg Tyr Asp Gly Ile His Tyr Leu Asp Ile Val Asp Cys Lys Ser

1890 1895 1900

Tyr Asp Thr Gly Glu Val Lys Val Thr Ala Glu Asn Pro Glu Gly Val

1905 1910 1915 1920

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

1925 1930 1935

Ser Val Leu Arg Arg Ala Pro Glu Pro Arg Pro Glu Phe His Val His

1940 1945 1950

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

1955 1960 1965

Asp Thr Thr Glu Thr Lys Glu Val Val Lys Leu Lys Arg Ala Glu Arg

1970 1975 1980

Ile Thr His Glu Lys Val Pro Glu Glu Ser Glu Glu Leu Arg Ser Lys

1985 1990 1995 2000

Phe Lys Arg Arg Thr Glu Glu Gly Tyr Tyr Glu Ala Ile Thr Ala Val

2005 2010 2015

Glu Leu Lys Ser Arg Lys Lys Asp Glu Ser Tyr Glu Glu Leu Leu Arg

2020 2025 2030

Lys Thr Lys Asp Glu Leu Leu His Trp Thr Lys Glu Leu Thr Glu Glu

2035 2040 2045

Glu Lys Lys Ala Leu Ala Glu Glu Gly Lys Ile Thr Ile Pro Thr Phe

2050 2055 2060

Lys Pro Asp Lys Ile Glu Leu Ser Pro Ser Met Glu Ala Pro Lys Ile

2065 2070 2075 2080

Phe Glu Arg Ile Gln Ser Gln Thr Val Gly Gln Gly Ser Asp Ala His

2085 2090 2095

Phe Arg Val Arg Val Val Gly Lys Pro Asp Pro Glu Cys Glu Trp Tyr

2100 2105 2110

Lys Asn Gly Val Lys Ile Glu Arg Ser Asp Arg Ile Tyr Trp Tyr Trp

2115 2120 2125

Pro Glu Asp Asn Val Cys Glu Leu Val Ile Arg Asp Val Thr Ala Glu

2130 2135 2140

Asp Ser Ala Ser Ile Met Val Lys Ala Ile Asn Ile Ala Gly Glu Thr

2145 2150 2155 2160

Ser Ser His Ala Phe Leu Leu Val Gln Ala Lys Gln Leu Ile Thr Phe

2165 2170 2175

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

2180 2185 2190

Thr Phe Glu Cys Glu Thr Ser Glu Pro Phe Val Lys Val Lys Trp Tyr

2195 2200 2205

Lys Asp Gly Met Glu Val His Glu Gly Asp Lys Tyr Arg Met His Ser

2210 2215 2220

Asp Arg Lys Val His Phe Leu Ser Ile Leu Thr Ile Asp Thr Ser Asp

2225 2230 2235 2240

Ala Glu Asp Tyr Ser Cys Val Leu Val Glu Asp Glu Asn Val Lys Thr

2245 2250 2255

Thr Ala Lys Leu Ile Val Glu Gly Ala Val Val Glu Phe Val Lys Glu

2260 2265 2270

Leu Gln Asp Ile Glu Val Pro Glu Ser Tyr Ser Gly Glu Leu Glu Cys

2275 2280 2285

Ile Val Ser Pro Glu Asn Ile Glu Gly Lys Trp Tyr His Asn Asp Val

2290 2295 2300

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

2305 2310 2315 2320

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

2325 2330 2335

Ser Phe Val Ile Asp Gly Lys Lys Thr Thr Cys Lys Leu Lys Met Lys

2340 2345 2350

Pro Arg Pro Ile Ala Ile Leu Gln Gly Leu Ser Asp Gln Lys Val Cys

2355 2360 2365

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

2370 2375 2380

Glu Gly Val Trp Met Lys Asp Gly Gln Glu Val Gln Pro Ser Asp Arg

2385 2390 2395 2400

Val His Ile Val Ile Asp Lys Gln Ser His Met Leu Leu Ile Glu Asp

2405 2410 2415

Met Thr Lys Glu Asp Ala Gly Asn Tyr Ser Phe Thr Ile Pro Ala Leu

2420 2425 2430

Gly Leu Ser Thr Ser Gly Arg Val Ser Val Tyr Ser Val Asp Val Ile

2435 2440 2445

Thr Pro Leu Lys Asp Val Asn Val Ile Glu Gly Thr Lys Ala Val Leu

2450 2455 2460

Glu Cys Lys Val Ser Val Pro Asp Val Thr Ser Val Lys Trp Tyr Leu

2465 2470 2475 2480

Asn Asp Glu Gln Ile Lys Pro Asp Asp Arg Val Gln Ala Ile Val Lys

2485 2490 2495

Gly Thr Lys Gln Arg Leu Val Ile Asn Arg Thr His Ala Ser Asp Glu

2500 2505 2510

Gly Pro Tyr Lys Leu Ile Val Gly Arg Val Glu Thr Asn Cys Asn Leu

2515 2520 2525

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

2530 2535 2540

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

2545 2550 2555 2560

Ile Asp Val Leu Trp Asn Phe Lys Asp Lys Glu Ile Lys Pro Ser Ser

2565 2570 2575

Lys Tyr Lys Ile Glu Ala His Gly Lys Ile Tyr Lys Leu Thr Val Leu

2580 2585 2590

Asn Met Met Lys Asp Asp Glu Gly Lys Tyr Thr Phe Tyr Ala Gly Glu

2595 2600 2605

Asn Met Thr Ser Gly Lys Leu Thr Val Ala Gly Gly Ala Ile Ser Lys

2610 2615 2620

Pro Leu Thr Asp Gln Thr Val Ala Glu Ser Gln Glu Ala Val Phe Glu

2625 2630 2635 2640

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

2645 2650 2655

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

2660 2665 2670

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

2675 2680 2685

Tyr Thr Tyr Lys Val Ala Thr Ser Lys Thr Ser Ala Lys Leu Lys Val

2690 2695 2700

Glu Ala Val Lys Ile Lys Lys Thr Leu Lys Asn Leu Thr Val Thr Glu

2705 2710 2715 2720

Thr Gln Asp Ala Val Phe Thr Val Glu Leu Thr His Pro Asn Val Lys

2725 2730 2735

Gly Val Gln Trp Ile Lys Asn Gly Val Val Leu Glu Ser Asn Glu Lys

2740 2745 2750

Tyr Ala Ile Ser Val Lys Gly Thr Ile Tyr Ser Leu Arg Ile Lys Asn

2755 2760 2765

Cys Ala Ile Val Asp Glu Ser Val Tyr Gly Phe Arg Leu Gly Arg Leu

2770 2775 2780

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

2785 2790 2795 2800

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

2805 2810 2815

Ser Val Ser His Asp Thr Val Pro Val Lys Trp Phe His Lys Ser Val

2820 2825 2830

Glu Ile Lys Pro Ser Asp Lys His Arg Leu Val Ser Glu Arg Lys Val

2835 2840 2845

His Lys Leu Met Leu Gln Asn Ile Ser Pro Ser Asp Ala Gly Glu Tyr

2850 2855 2860

Thr Ala Val Val Gly Gln Leu Glu Cys Lys Ala Lys Leu Phe Val Glu

2865 2870 2875 2880

Thr Leu His Ile Thr Lys Thr Met Lys Asn Ile Glu Val Pro Glu Thr

2885 2890 2895

Lys Thr Ala Ser Phe Glu Cys Glu Val Ser His Phe Asn Val Pro Ser

2900 2905 2910

Met Trp Leu Lys Asn Gly Val Glu Ile Glu Met Ser Glu Lys Phe Lys

2915 2920 2925

Ile Val Val Gln Gly Lys Leu His Gln Leu Ile Ile Met Asn Thr Ser

2930 2935 2940

Thr Glu Asp Ser Ala Glu Tyr Thr Phe Val Cys Gly Asn Asp Gln Val

2945 2950 2955 2960

Ser Ala Thr Leu Thr Val Thr Pro Ile Met Ile Thr Ser Met Leu Lys

2965 2970 2975

Asp Ile Asn Ala Glu Glu Lys Asp Thr Ile Thr Phe Glu Val Thr Val

2980 2985 2990

Asn Tyr Glu Gly Ile Ser Tyr Lys Trp Leu Lys Asn Gly Val Glu Ile

2995 3000 3005

Lys Ser Thr Asp Lys Cys Gln Met Arg Thr Lys Lys Leu Thr His Ser

3010 3015 3020

Leu Asn Ile Arg Asn Val His Phe Gly Asp Ala Ala Asp Tyr Thr Phe

3025 3030 3035 3040

Val Ala Gly Lys Ala Thr Ser Thr Ala Thr Leu Tyr Val Glu Ala Arg

3045 3050 3055

His Ile Glu Phe Arg Lys His Ile Lys Asp Ile Lys Val Leu Glu Lys

3060 3065 3070

Lys Arg Ala Met Phe Glu Cys Glu Val Ser Glu Pro Asp Ile Thr Val

3075 3080 3085

Gln Trp Met Lys Asp Asp Gln Glu Leu Gln Ile Thr Asp Arg Ile Lys

3090 3095 3100

Ile Gln Lys Glu Lys Tyr Val His Arg Leu Leu Ile Pro Ser Thr Arg

3105 3110 3115 3120

Met Ser Asp Ala Gly Lys Tyr Thr Val Val Ala Gly Gly Asn Val Ser

3125 3130 3135

Thr Ala Lys Leu Phe Val Glu Gly Arg Asp Val Arg Ile Arg Ser Ile

3140 3145 3150

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

3155 3160 3165

Glu Val Asn Glu Asp Asp Val Asp Ala His Trp Tyr Lys Asp Gly Ile

3170 3175 3180

Glu Ile Asn Phe Gln Val Gln Glu Arg His Lys Tyr Val Val Glu Arg

3185 3190 3195 3200

Arg Ile His Arg Met Phe Ile Ser Glu Thr Arg Gln Ser Asp Ala Gly

3205 3210 3215

Glu Tyr Thr Phe Val Ala Gly Arg Asn Arg Ser Ser Val Thr Leu Tyr

3220 3225 3230

Val Asn Ala Pro Glu Pro Pro Gln Val Leu Gln Glu Leu Gln Pro Val

3235 3240 3245

Thr Val Gln Ser Gly Lys Pro Ala Arg Phe Cys Ala Val Ile Ser Gly

3250 3255 3260

Arg Pro Gln Pro Lys Ile Ser Trp Tyr Lys Glu Glu Gln Leu Leu Ser

3265 3270 3275 3280

Thr Gly Phe Lys Cys Lys Phe Leu His Asp Gly Gln Glu Tyr Thr Leu

3285 3290 3295

Leu Leu Ile Glu Ala Phe Pro Glu Asp Ala Ala Val Tyr Thr Cys Glu

3300 3305 3310

Ala Lys Asn Asp Tyr Gly Val Ala Thr Thr Ser Ala Ser Leu Ser Val

3315 3320 3325

Glu Val Pro Glu Val Val Ser Pro Asp Gln Glu Met Pro Val Tyr Pro

3330 3335 3340

Pro Ala Ile Ile Thr Pro Leu Gln Asp Thr Val Thr Ser Glu Gly Gln

3345 3350 3355 3360

Pro Ala Arg Phe Gln Cys Arg Val Ser Gly Thr Asp Leu Lys Val Ser

3365 3370 3375

Trp Tyr Ser Lys Asp Lys Lys Ile Lys Pro Ser Arg Phe Phe Arg Met

3380 3385 3390

Thr Gln Phe Glu Asp Thr Tyr Gln Leu Glu Ile Ala Glu Ala Tyr Pro

3395 3400 3405

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

3410 3415 3420

Val Ser Ser Thr Ala Asn Leu Ser Leu Glu Ala Pro Glu Ser Ile Leu

3425 3430 3435 3440

His Glu Arg Ile Glu Gln Glu Ile Glu Met Glu Met Lys Glu Leu Phe

3445 3450 3455

Ser Glu Gly Glu Ser Glu His Ser Glu Arg Asp Thr Arg Asp Ala Phe

3460 3465 3470

Ser Asp Ser Glu Asp Ile Asp His Lys Ser Met Ala Ala Lys Arg Tyr

3475 3480 3485

Ala Ser Arg Ile Ser Ser Thr Ser Ser Trp Pro Glu Tyr Phe Lys Pro

3490 3495 3500

Ser Phe Thr Gln Lys Leu Thr Phe Lys Tyr Val Leu Glu Gly Glu Pro

3505 3510 3515 3520

Val Val Phe Thr Cys Arg Leu Ile Ala Cys Pro Thr Pro Glu Met Thr

3525 3530 3535

Trp Phe His Asn Asn Arg Pro Ile Pro Thr Gly Leu Arg Arg Ile Ile

3540 3545 3550

Lys Ala Glu Ser Asp Leu His His His Ser Ser Ser Leu Glu Ile Lys

3555 3560 3565

Arg Val Gln Asp Arg Asp Ser Gly Ser Tyr Arg Leu Leu Ala Ile Asn

3570 3575 3580

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

3585 3590 3595 3600

Gly Gln Asp Glu Lys Tyr Leu Glu Phe Leu Lys Arg Ala Glu Arg Thr

3605 3610 3615

His Glu Asn Val Glu Ala Leu Val Glu Arg Gly Glu Asp Arg Ile Lys

3620 3625 3630

Val Asp Leu Arg Phe Thr Gly Ser Pro Phe Asn Lys Lys Gln Asp Val

3635 3640 3645

Glu Gln Lys Gly Met Met Arg Thr Ile His Phe Lys Thr Met Ser Ser

3650 3655 3660

Ala Lys Lys Thr Asp Tyr Met Tyr Asp Glu Glu Tyr Leu Glu Ser Lys

3665 3670 3675 3680

Ser Asp Ile Arg Gly Trp Leu Asn Val Gly Glu Ser Phe Leu Asp Lys

3685 3690 3695

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

3700 3705 3710

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

3715 3720 3725

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

3730 3735 3740

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

3745 3750 3755 3760

Lys Val Asp His Ser Ala Glu Ser Ile Val Gln Asn Pro His Ala Leu

3765 3770 3775

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

3780 3785 3790

Phe Gln Thr Ile Val Asp Glu Glu Ile Phe Gln Thr Glu Ile Arg Met

3795 3800 3805

Ser Gln Glu Ala Leu Val Lys Glu Ser Leu Pro Lys Asp His Leu Tyr

3810 3815 3820

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

3825 3830 3835 3840

Glu Ile Met Ala Asn Thr Thr Ile Gly Glu Ser Ser Thr Tyr Ile Thr

3845 3850 3855

Asn Val Cys Glu Lys Glu Glu Val Tyr Glu Thr Pro Glu Asn Val Ser

3860 3865 3870

Gln Ala Ile Thr Pro His Ala Ser Glu Ser Phe Gly Thr Leu Val Asn

3875 3880 3885

Val Glu Glu Ser Glu Glu Ile Ala Ser Glu Arg Ile Lys Lys Asp Asp

3890 3895 3900

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

3905 3910 3915 3920

Thr Glu Gln Lys Glu Glu Asn Met Arg Phe Phe Glu Asn Ser Phe Arg

3925 3930 3935

Lys Arg Pro Gln Arg Cys Pro Pro Ser Phe Leu Gln Glu Ile Glu Ser

3940 3945 3950

Gln Glu Val Tyr Glu Gly Asp Ser Cys Asn Phe Val Cys His Phe Gln

3955 3960 3965

Gly Tyr Pro Gln Pro Ile Val Thr Trp Tyr Asn Asn Asp Met Pro Ile

3970 3975 3980

Pro Arg Asn Gln Asn Phe Ile Ile His Ser Leu Glu Asn Tyr Ser Ile

3985 3990 3995 4000

Leu Thr Leu Ser Ser Val His His Gln Asn Glu Gly Ser Ile Thr Cys

4005 4010 4015

Val Leu Phe Asn Gln Tyr Gly Thr Val Lys Thr Thr Ser Met Leu Lys

4020 4025 4030

Val Lys Ala Lys Gln Lys His Asp Val Lys Ala His Lys Val Pro Val

4035 4040 4045

Phe His Asp Tyr Leu Asp Glu Glu Glu Glu Leu Ala Leu Val Phe Asp

4050 4055 4060

Gln Ala Lys Gly Ala His Pro Ser Met Ser Gln Glu Gly Gln Thr Asn

4065 4070 4075 4080

Leu His Leu Leu Lys Thr Asn Pro Pro Val Pro Pro Ser Gly Asp Thr

4085 4090 4095

Glu Leu Leu Ser Phe Pro Val Glu Ile Gln Val Thr Ala Ala Thr Pro

4100 4105 4110

Ile Pro Glu Gln Asp Lys Glu Ser Lys Glu Val Phe Gln Thr Glu Glu

4115 4120 4125

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

4130 4135 4140

His Arg Phe Val Phe Leu Ser Asp Ile Thr Asn Glu Pro Pro Lys Met

4145 4150 4155 4160

Leu Gln Glu Met Pro Lys His Ala Arg Cys Arg Glu Gly Asp Ser Ile

4165 4170 4175

Ile Leu Glu Cys Leu Ile Ser Gly Glu Pro Gln Pro Val Val Thr Trp

4180 4185 4190

Phe Gln Asn Gly Val Leu Leu Lys Gln Asn Gln Lys Phe Gln Phe Glu

4195 4200 4205

Glu Val Asn Cys Ser His Gln Leu Tyr Ile Lys Asp Val Asn Ser Gln

4210 4215 4220

Asp Ser Gly Lys Tyr Lys Cys Val Ala Glu Asn Asn Ser Gly Ala Val

4225 4230 4235 4240

Glu Ser Val Ser Asp Leu Thr Val Glu Pro Val Thr Tyr Arg Glu Asn

4245 4250 4255

Ser Gln Phe Glu Asn Ile Gly Glu Ile Tyr Gly Lys Tyr Ser Arg Asp

4260 4265 4270

Gln Gln Leu Gln Asp Gln Gly Glu Ser Val Arg Ala His Phe Tyr Asp

4275 4280 4285

Tyr Pro Ala Gly Pro Phe Thr Pro Trp Thr Asn Val Lys Glu Tyr Ser

4290 4295 4300

Val Arg Asp Tyr Phe Gln Ser Leu Glu Thr Ile Glu Gln Ile Asp Gln

4305 4310 4315 4320

Lys Glu Gln Val Arg Cys Ile Pro Ser Arg Glu Lys Ile Pro Arg Phe

4325 4330 4335

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

4340 4345 4350

Glu Phe Ile Gln Cys Gln Ala Glu Gly Lys Glu Arg His Val Ser Glu

4355 4360 4365

Lys Ser Lys Leu His Gln Ala Glu Gly Thr Val Tyr Pro Phe Val Asp

4370 4375 4380

Asp Phe Ser Asp Val Thr Ile Lys Lys Glu Ile Arg Asn Asn Phe Gly

4385 4390 4395 4400

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

4405 4410 4415

Asp Tyr Leu Pro Asn Ile His Ser Glu Arg Ile Ser Asp Ser Tyr Asn

4420 4425 4430

Thr Lys Asp Ser Ser Ala Ile Val Tyr Glu Glu Ser Leu Gly Glu Glu

4435 4440 4445

Ile His Tyr Pro Gly Lys Lys Val Lys His Arg Ile Ile Glu Phe Glu

4450 4455 4460

Lys Leu His Val Glu Lys Gly Val Leu Glu Lys Arg Pro Thr Arg Thr

4465 4470 4475 4480

Ser Ile Val Asn Pro Pro Gln Lys Lys Ile Asp Asp Lys Ala Phe Ser

4485 4490 4495

Leu Lys Gln Arg Glu Ser Arg Ser Ser Asn Leu Asn Ala Asn Met Tyr

4500 4505 4510

Gln Ala Glu Lys Met Ser Pro Asn Thr Glu Ser Asp Ser Ser Asn Ile

4515 4520 4525

Ala Ile Asn Leu Lys Leu Leu Ser Ser Gln Thr His Lys Glu Phe Asp

4530 4535 4540

Ala Gln Glu Arg Glu Gln Gln Glu Lys Ile Ser Leu Ile Asp Lys Pro

4545 4550 4555 4560

Ala Ile Ser Lys Arg Ala Glu His Glu Ser Pro Ile Thr Phe Asp Leu

4565 4570 4575

Lys Gln Phe His Thr Gln Ile Lys His Thr Asp Val Lys Phe Gln Glu

4580 4585 4590

Leu Asp Ser Gly Gln Pro Glu Glu Ala Tyr Phe Lys Ile Gln His Pro

4595 4600 4605

Ala Asp Thr Glu Asn Ile Val Phe Asp Leu Lys Gln Met Tyr Ser His

4610 4615 4620

Ile Gly Asp Pro Ala Leu Glu Phe Gln Gly Gln Glu Thr Arg Glu Gln

4625 4630 4635 4640

Gln Glu Ile His Tyr Lys Glu Lys Ile Pro Ser Pro Glu Thr Leu Gln

4645 4650 4655

Pro Asp Thr His Asn Ile Ser Lys Ser Val Gln Asn Asn Val Phe Ala

4660 4665 4670

Ser Gln Glu Ile Ser Ser Ser Gln Glu Leu Ser Asn Arg Thr Met Val

4675 4680 4685

Glu Lys Ser Ser Ile Asp Glu Asn Ser Ile Ser Leu Glu Lys Glu Val

4690 4695 4700

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

4705 4710 4715 4720

Leu Lys Ser Phe Ser Glu Glu Ile Tyr Ser Glu Ser Cys Ala Leu Leu

4725 4730 4735

Pro Thr Ser Ser Ala Asp Ile Glu Glu Thr Asp Leu Ser Glu Lys Ser

4740 4745 4750

Cys Pro Leu Glu Asn Gly Gly Arg Ser Ser Ile Ser His Leu Lys Lys

4755 4760 4765

Ala Ala Ser Glu Glu Lys Pro Leu Gly Val Gly Glu Met Glu Glu Glu

4770 4775 4780

Cys Thr Leu Glu Pro Glu Leu Ala Ala Phe Pro Lys Gln Asp Gly Gly

4785 4790 4795 4800

Thr Gln Glu Tyr Thr Asp Ala Thr Leu Glu Asp His Arg Gly Asp Val

4805 4810 4815

Gln Glu Ala Asp Thr Leu His Arg Gln Leu Ser Leu Ser Gln Cys Phe

4820 4825 4830

Pro Leu Leu Met Thr Glu Glu Gln Gln Asn Pro Gly Glu Gln Ile Ser

4835 4840 4845

Thr Asn Ile His Ala Ser Gly Glu Glu Lys Cys Tyr Glu Glu Val Gln

4850 4855 4860

Val Gln Asn Glu Ala Ser Phe Ser Thr Leu Glu Gly Glu Met Ile Glu

4865 4870 4875 4880

Thr Ser Phe Ser Gln Asn Ile Pro Lys Leu Asp Glu Ala His Thr Thr

4885 4890 4895

Glu Ala Ala Glu Ser Glu Thr Ser Leu Thr Gln Tyr Leu Leu Ala Ala

4900 4905 4910

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

4915 4920 4925

Leu Val Gln Ser Glu Ser Ile Thr Ser Met Glu Val Glu Glu Val Thr

4930 4935 4940

Phe Asn Thr Val Tyr Glu Tyr Tyr Asn Gln Lys Gln Glu Ser Leu Gly

4945 4950 4955 4960

Arg Pro Leu Ser Pro Glu Ser Asp Ile Ser Ile Gly Val Gly Ser Thr

4965 4970 4975

Thr Ser Glu Glu Ile Ser Glu Leu Asp Gln Phe Tyr Thr Pro Pro Ser

4980 4985 4990

Ser Val Glu Tyr Phe Glu Ser Pro Lys Ser Pro Asp Leu Tyr Phe Asn

4995 5000 5005

Pro Ser Asp Ile Thr Lys Gln Ser Ser Ile His Ser Gly Gly Glu Thr

5010 5015 5020

Val Glu Arg Tyr Ser Thr Pro Leu Gly Glu Val Ala Glu Arg Tyr Ser

5025 5030 5035 5040

Thr Pro Ser Glu Gly Glu Val Gly Glu Arg Tyr Ser Thr Pro Pro Gly

5045 5050 5055

Glu Thr Leu Glu Arg Tyr Ser Thr Pro Pro Gly Glu Thr Leu Glu Arg

5060 5065 5070

Tyr Ser Thr Pro Pro Gly Glu Thr Leu Glu Arg Tyr Ser Thr Pro Pro

5075 5080 5085

Gly Glu Thr Leu Glu Arg Tyr Ser Thr Pro Pro Gly Glu Thr Leu Glu

5090 5095 5100

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

5105 5110 5115 5120

Thr Gly Gly Pro Asn Pro Thr Gly Thr Phe Lys Thr Tyr Pro Ser Lys

5125 5130 5135

Ile Glu Arg Glu Asp Gly Thr Pro Asn Glu His Phe Tyr Thr Pro Thr

5140 5145 5150

Glu Glu Arg Gly Ser Ala Tyr Glu Ile Trp Arg Ser Asp Ser Phe Gly

5155 5160 5165

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

5170 5175 5180

Phe Ile Glu Pro Leu Thr Lys Arg Lys Val Tyr Glu Asn Thr Thr Leu

5185 5190 5195 5200

Gly Phe Ile Val Glu Val Glu Gly Leu Pro Val Pro Gly Val Lys Trp

5205 5210 5215

Tyr Arg Asn Lys Ser Leu Leu Glu Pro Asp Glu Arg Ile Lys Met Glu

5220 5225 5230

Arg Val Gly Asn Val Cys Ser Leu Glu Ile Ser Asn Ile Gln Lys Gly

5235 5240 5245

Glu Gly Gly Glu Tyr Met Cys His Ala Val Asn Ile Ile Gly Glu Ala

5250 5255 5260

Lys Ser Phe Ala Asn Val Asp Ile Met Pro Gln Glu Glu Arg Val Val

5265 5270 5275 5280

Ala Leu Pro Pro Pro Val Thr His Gln His Val Met Glu Phe Asp Leu

5285 5290 5295

Glu His Thr Thr Ser Ser Arg Thr Pro Ser Pro Gln Glu Ile Val Leu

5300 5305 5310

Glu Val Glu Leu Ser Glu Lys Asp Val Lys Glu Phe Glu Lys Gln Val

5315 5320 5325

Lys Ile Val Thr Val Pro Glu Phe Thr Pro Asp His Lys Ser Met Ile

5330 5335 5340

Val Ser Leu Asp Val Leu Pro Phe Asn Phe Val Asp Pro Asn Met Asp

5345 5350 5355 5360

Ser Arg Glu Gly Glu Asp Lys Glu Leu Lys Ile Asp Leu Glu Val Phe

5365 5370 5375

Glu Met Pro Pro Arg Phe Ile Met Pro Ile Cys Asp Phe Lys Ile Pro

5380 5385 5390

Glu Asn Ser Asp Ala Val Phe Lys Cys Ser Val Ile Gly Ile Pro Thr

5395 5400 5405

Pro Glu Val Lys Trp Tyr Lys Glu Tyr Met Cys Ile Glu Pro Asp Asn

5410 5415 5420

Ile Lys Tyr Val Ile Ser Glu Glu Lys Gly Ser His Thr Leu Lys Ile

5425 5430 5435 5440

Arg Asn Val Cys Leu Ser Asp Ser Ala Thr Tyr Arg Cys Arg Ala Val

5445 5450 5455

Asn Cys Val Gly Glu Ala Ile Cys Arg Gly Phe Leu Thr Met Gly Asp

5460 5465 5470

Ser Glu Ile Phe Ala Val Ile Ala Lys Lys Ser Lys Val Thr Leu Ser

5475 5480 5485

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

5490 5495 5500

Phe Glu Phe Gln Val Val Glu Gly Pro Pro Arg Phe Ile Lys Gly Ile

5505 5510 5515 5520

Ser Asp Cys Tyr Ala Pro Ile Gly Thr Ala Ala Tyr Phe Gln Cys Leu

5525 5530 5535

Val Arg Gly Ser Pro Arg Pro Thr Val Tyr Trp Tyr Lys Asp Gly Lys

5540 5545 5550

Leu Val Gln Gly Arg Arg Phe Thr Val Glu Glu Ser Gly Thr Gly Phe

5555 5560 5565

His Asn Leu Phe Ile Thr Ser Leu Val Lys Ser Asp Glu Gly Glu Tyr

5570 5575 5580

Arg Cys Val Ala Thr Asn Lys Ser Gly Met Ala Glu Ser Phe Ala Ala

5585 5590 5595 5600

Leu Thr Leu Thr

<210> 5

<211> 19

<212> DNA

<213> homo sapiens

<400> 5

ttgaaatgcc tcctcgctt 19

<210> 6

<211> 23

<212> DNA

<213> homo sapiens

<400> 6

ccatctttgt accagtaaac cgt 23

Claims (2)

1.突变的肥厚型心肌病致病基因TTN，其特征在于，与野生型TTN基因编码DNA的参考序列SEQ ID NO:3相比，第16469位点的碱基T突变为碱基G。

2.根据权利要求1所述的突变的肥厚型心肌病致病基因TTN，其特征在于，在基因组位置chr2:179610620-chr2:179610669处，序列为SEQ ID NO:2。

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