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Mutation detection of cardiac ion channel genes in sudden death cases

猝死病例心脏离子通道基因突变检测

基本信息

批准号：
11470121
负责人：
SUZUKI Koichi
金额：
$ 8.32万
依托单位：
Osaka Medical College
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2001
项目状态：
已结题

项目摘要

In the sudden death of a young adult, which is unexplained by a morphorogical examination and is unexpected by past history, we contructed a working theory that ion channels expressed in cardiac conducting system may be involved in the sudden death because long QT syndrome (LQT) has been shown to be caused by mutations in various ion channel genes.HERG, KVLQT, and SCN5A of which mutations cause LQT, and Kir6.2, GIRK1, GIRK4, and MAXIK were analyzed for mutations in eight sudden death cases and 100 healthy controls. A C to T transition in an intron of GIRK4 was found to be the only candidate mutation for sudden death on the basis of the function of the GIRK4 associated channel (I_<KACh>). The transition was assumed to change the splice donor site, leading to premature introduction of stop codon in the following exon. The mRNA was expected to be 5 bp longer than usual one. RT-PCR of ectopically expressed mRNA in leucocytes recovered from a healthy individual homozygous for the mutation failed to show the longer mRNA but this result does not mean that the presumed splice variant is not produced in impulse' conducting system. Only a small fraction of the truncated GIRK4 must decrease the I_<KACh> channel by dominant negative effect, thus resulting in functional impairment of the I_<KACh> channel.In addition to the GIRK4 mutation, several polymorphic mutations were identified in the other channel genes but all of them were found to be neutral variants. In this study, mutation has not been searched for along the total length of the genes. Further screening for mutation of the genes will be required.

在一例青年猝死病例中，我们发现心脏传导系统表达的离子通道可能参与了猝死的发生，这是因为长QT综合征（LQT）是由多种离子通道基因突变引起的，其中HERG、KVLQT和SCN 5A突变引起LQT，Kir6.2突变引起LQT，在8例猝死病例和100例健康对照中分析了GIRK 1、GIRK 4和MAXIK的突变。基于GIRK 4相关通道（I_）的功能，发现GIRK 4内含子中的C至T转换是猝死的唯一候选突变<KACh>。假设该转换改变剪接供体位点，导致终止密码子在随后的外显子中过早引入。结果表明，扩增的mRNA比正常的mRNA长5 bp。从突变纯合子的健康个体回收的白细胞中的异位表达mRNA的RT-PCR未能显示较长的mRNA，但这一结果并不意味着假定的剪接变体不在冲动传导系统中产生。GIRK 4基因的突变导致I<KACh>_通道功能受损<KACh>，除GIRK 4突变外，在其他通道基因中也发现了一些多态性突变，但均为中性突变。在这项研究中，突变没有沿着基因的总长度进行沿着搜索。需要进一步筛查基因突变。