Novel KCNE3 Mutation Reduces Repolarizing Potassium Current and Associated With Long QT Syndrome
Novel KCNE3 Mutation Reduces Repolarizing Potassium Current and Associated With Long QT Syndrome
复制标题
DOI：
10.1002/humu.20834
复制
发表时间：
2009-04-01
期刊：
影响因子：
3.9
通讯作者：
Horie, Minoru
中科院分区：
文献类型：
--
作者：
Ohno, Seiko;Toyoda, Futoshi;Horie, Minoru
长QT综合征（LQTS）是一种遗传性疾病，涉及编码许多心脏离子通道和膜接头蛋白的基因突变。在负责LQTS的基因中，KCNE 1和KCNE 2是KCNE基因家族的成员，并作为Kv通道的辅助亚基发挥作用。第三个KCNE基因KCNE 3在心肌细胞中表达，并与KCNQ 1相互作用以改变通道特性。然而，KCNE 3从未与LQTS相关联。为了研究KCNE 3与LQTS之间的关联，我们使用DHPLC-WAVE系统和直接测序对485名日本LQTS先证者进行了KCNE 3突变和单核苷酸多态性（SNP）的遗传筛查。因此，我们确定了两个KCNE 3错义突变，位于N-和C-末端结构域。通过使用稳定表达KCNQ 1的CHO细胞的异源表达系统检查这些突变的功能效应。在一名76岁女性患者中发现了一种突变p.R99 λ H，该患者在丙吡胺给药后发生尖端扭转型室性心动过速（TdP）。另一种突变p.T4A在一名16岁男孩和一名67岁妇女中被发现。尽管这名男孩携带另一种KCNH 2突变，但他没有症状。另一方面，该女性患有低钾血症引起的TdP。在一系列的电生理分析中，KCNQ_1（Q_1）+KCNE_3（E_3）-R_（99）λ H通道与Q_1 + E_3-WT相比，显著降低了外向电流，而Q_1 + E_3-T_4A通道的电流密度无统计学意义。这是首次报道与LQTS相关的KCNE 3突变。筛查KCNE 3基因的变异对LQTS患者具有重要的临床意义。《Mutat》30，557-563，2009年。(C)2009 Wiley-Liss，Inc.
Long QT syndrome (LQTS) is an inherited disease involving Mutations in the genes encoding a number of cardiac ion channels and a membrane adaptor protein. Among the genes that are responsible for LQTS, KCNE1 and KCNE2 are members of the KCNE family of genes, and function as ancillary subunits of Kv channels. The third KCNE gene, KCNE3, is expressed in cardiac myocytes and interacts with KCNQ1 to change the channel properties. However, KCNE3 has never been linked to LQTS. To investigate the association between KCNE3 and LQTS, we conducted a genetic screening of KCNE3 mutations and single nucleotide polymorphisms (SNPs) in 485 Japanese LQTS probands using DHPLC-WAVE system and direct sequencing. Consequently, we identified two KCNE3 missense mutations, located in the N- and C-terminal domains. The functional effects of these mutations were examined by heterologous expression systems using CHO cells stably expressing KCNQ1. One mutation, p.R99 lambda H was identified in a 76-year-old woman who suffered torsades de pointes (TdP) after administration of disopyramide. Another Mutation, p.T4A was identified in a 16-year-old boy and 67-year-old woman. Although the boy carried another KCNH2 mutation, he was asymptomatic. On the other hand, the woman suffered from hypokalemia-induced TdP. In a series of electrophysiological analyses, the KCNQ1(Q1) +KCNE3 (E3)-R99 lambda H channel significantly reduced Out, ward current compared to Q1+E3-WT, though the cur-rent density of the Q1+E3-T4A channel displayed no statistical significance. This is the first report of KCNE3 mutations associated with LQTS. Screening for variants in the KCNE3 gene is of clinical importance for LQTS patients. Hum Mutat 30, 557-563, 2009. (C) 2009 Wiley-Liss, Inc.