Identification of a Kir3.4 Mutation in Congenital Long QT Syndrome
Identification of a Kir3.4 Mutation in Congenital Long QT Syndrome
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DOI：
10.1016/j.ajhg.2010.04.017
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发表时间：
2010-06-11
影响因子：
9.8
通讯作者：
Chen, Yi-Han
中科院分区：
文献类型：
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作者：
Yang, Yanzong;Yang, Yiqing;Chen, Yi-Han
先天性长QT间期综合征(LQTS)是一种遗传性疾病，继发于致命性心律失常而导致心源性猝死。虽然LQTS的基因很多，但仍有30%-40%的病例病因不明。本研究对一个常染色体显性LQTS中国大家族(四代，49个个体)进行了临床研究。利用多态微卫星标记定位遗传位点，进行全基因组连锁分析，并通过测序筛选候选基因。用Western blotting和膜片钳电生理方法研究突变蛋白的表达模式和功能特性。LQTS相关基因的遗传位点被定位在染色体11q23.3-24.3。在KCNJ5基因编码的G蛋白偶联的内向整流钾通道亚基Kir3.4中发现一个杂合突变(Kir3.4-Gly387Arg)。Kir3.4-Gly387Arg突变在所有9个受影响的家庭成员中都存在，而在528个种族匹配的对照组中没有。人心脏组织的Western blotting显示，Kir3.4在心室有显著的表达水平。用Kir3.4-Gly387Arg进行的异源表达研究表明，由于质膜表达减少，导致了功能丧失的电生理表型。我们的发现提示Kir3.4在LQTS的病因学中起作用。
Congenital long QT syndrome (LQTS) is a hereditary disorder that leads to sudden cardiac death secondary to fatal cardiac arrhythmias. Although many genes for LQTS have been described, the etiology remains unknown in 30%-40% of cases. In the present study, a large Chinese family (four generations, 49 individuals) with autosomal-dominant LQTS was clinically evaluated. Genome-wide linkage analysis was performed by using polymorphic microsatellite markers to map the genetic locus, and positional candidate genes were screened by sequencing for mutations. The expression pattern and functional characteristics of the mutated protein were investigated by western blotting and patch-clamp electrophysiology. The genetic locus of the LQTS-associated gene was mapped to chromosome 11q23.3-24.3. A heterozygous mutation (Kir3.4-Gly387Arg) was identified in the G protein-coupled, inwardly rectifying potassium channel subunit Kir3.4, encoded by the KCNJ5 gene. The Kir3.4-Gly387Arg mutation was present in all nine affected family members and absent in 528 ethnically matched controls. Western blotting of human cardiac tissue demonstrated significant Kir3.4 expression levels in the cardiac ventricles. Heterologous expression studies with Kir3.4-Gly387Arg revealed a loss-of-function electrophysiological phenotype resulting from reduced plasma membrane expression. Our findings suggest a role for Kir3.4 in the etiology of LQTS.