Drug-induced Long-QT syndrome associated with a subclinical SCN5A mutation
Drug-induced Long-QT syndrome associated with a subclinical SCN5A mutation
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DOI：
10.1161/01.cir.0000027139.42087.b6
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发表时间：
2002-09-03
期刊：
影响因子：
37.8
通讯作者：
Kitabatake, A
中科院分区：
文献类型：
--
作者：
Makita, N;Horie, M;Kitabatake, A
背景-先天性长QT间期综合征(LQTS)相关基因的亚临床突变被认为是药物所致LQT间期综合征及其伴发的危及生命的心律失常的危险因素。最近的研究已经确定了心脏K+通道基因的遗传变异，使受影响的个体易患获得性LQTS。我们在一例药物诱导的LQTS患者中发现了一种新的Na+通道突变。方法和结果--一名老年妇女在使用促动力药物西沙必利治疗期间有记录的QT延长和尖端扭矩，我们对LQTS相关基因进行了突变分析。在心肌钠离子通道(SCN5A)的C末端区域发现了一个新的错义突变(L1825P)。在TSA-201细胞中异源表达的L1825P通道呈现缓慢衰变的Na+电流和显著的河豚毒素敏感的非失活成分，类似于SCN5A相关的先天性LQT(LQT3)最常见的功能获得表型。此外，L1825P还表现出Brugada综合征特有的Na+通道功能丧失特征。在表达L1825P的细胞中观察到的峰值Na+电流密度显著降低，激活和失活的电压依赖分别向更正和更负的电位移动。结论-本研究表明LQTS相关基因SCN5A的亚临床突变可能使某些人易患药物所致的心律失常。
Background-Subclinical mutations in genes associated with the congenital long-QT syndromes (LQTS) have been suggested as a risk factor for drug-induced LQTS and accompanying life-threatening arrhythmias. Recent studies have identified genetic variants of the cardiac K+ channel genes predisposing affected individuals to acquired LQTS. We have identified a novel Na+ channel mutation in an individual who exhibited drug-induced LQTS.Methods and Results-An elderly Japanese woman with documented QT prolongation and torsade de pointes during treatment with the prokinetic drug cisapride underwent mutational analysis of LQTS-related genes. A novel missense mutation (L1825P) was identified within the C-terminus region of the cardiac Na+ channel (SCN5A). The L1825P channel heterologously expressed in tsA-201 cells showed Na+ cur-rent with slow decay and a prominent tetrodotoxin-sensitive noninactivating component, similar to the gain-of-function phenotype most commonly observed for SCN5A-associated congenital LQTS (LQT3). In addition, L1825P exhibited loss of function Na+ channel features characteristic of Brugada syndrome. Peak Na+ current density observed in cells expressing L1825P was significantly diminished, and the voltage dependence of activation and inactivation was shifted toward more positive and negative potentials, respectively.Conclusions-This study demonstrates that subclinical mutations in the LQTS-related gene SCN5A may predispose certain individuals to drug-induced cardiac arrhythmias.