D85N, a KCNE1 Polymorphism, Is a Disease-Causing Gene Variant in Long QT Syndrome
D85N, a KCNE1 Polymorphism, Is a Disease-Causing Gene Variant in Long QT Syndrome
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DOI：
10.1016/j.jacc.2009.06.005
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发表时间：
2009-08-25
影响因子：
24
通讯作者：
Horie, Minoru
中科院分区：
文献类型：
--
作者：
Nishio, Yukiko;Makiyama, Takeru;Horie, Minoru
目的 本研究旨在探讨 KCNE1 多态性 D85N 是否是导致长 QT 综合征 (LQTS) 表型的基因变异。背景 KCNE1 编码心脏电压门控 K+ 通道的 β 亚基并引起 LQTS，其特征是 QT 间期延长和尖端扭转型室速（一种致命性心律失常）。 D85N 是 KCNE1 多态性，已知是与药物诱导的 LQTS 相关的功能变异。方法为了阐明这种多态性的患病率和临床意义，我们对 317 名 LQTS 先证者进行了基因筛查。为了进行比较，我们检查了 496 名健康对照受试者中的情况。我们还在哺乳动物细胞中对 D85N 变异进行了生物物理测定。结果 D85N 携带者的等位基因频率在健康人中为 0.81%。相比之下，在LQTS先证者中，有1名纯合子和23名杂合子携带者（等位基因频率为3.9%）。 23 名杂合子携带者中的 7 名在 LQTS 相关基因中存在额外突变，并且 3 名女性受试者记录了诱发该症状的因素。排除这些先证者后，与对照受试者相比，D85N 患病率显着更高（等位基因频率 2.1%，p < 0.05）。在一项中国仓鼠卵巢细胞的异源表达研究中，发现 KCNE1-D85N 对 KCNQ1 和 KCNH2 编码的通道电流产生显着的功能丧失作用。结论 KCNE1-D85N 多态性在我们的 LQTS 先证者中显着更频繁。该功能变异是 LQTS 表型的致病基因变异，通过与 KCNH2 和 KCNQ1 相互作用发挥作用。由于其等位基因频率在对照个体中接近 1%，因此 KCNE1-D85N 可能是临床上重要的遗传变异。 （J Am Coll Cardiol 2009；54：812-9）(C) 2009 年，美国心脏病学会基金会
Objectives This study aims to address whether D85N, a KCNE1 polymorphism, is a gene variant that causes long QT syndrome (LQTS) phenotype.Background KCNE1 encodes the beta-subunit of cardiac voltage-gated K+ channels and causes LQTS, which is characterized by the prolongation of the QT interval and torsades de pointes, a lethal arrhythmia. D85N, a KCNE1 polymorphism, is known to be a functional variant associated with drug-induced LQTS.Methods In order to elucidate the prevalence and clinical significance of this polymorphism, we performed genetic screening in 317 LQTS probands. For comparison, we examined its presence in 496 healthy control subjects. We also conducted biophysical assays for the D85N variant in mammalian cells.Results The allele frequency for D85N carriers was 0.81% in healthy people. In contrast, among LQTS probands, there were 1 homozygous and 23 heterozygous carriers (allele frequency 3.9%). Seven of 23 heterozygous carriers had additional mutations in LQTS-related genes, and 3 female subjects had documented factors predisposing to the symptom. After excluding these probands, the D85N prevalence was significantly higher compared with control subjects (allele frequency 2.1%, p < 0.05). In a heterologous expression study with Chinese hamster ovarian cells, KCNE1-D85N was found to exert significant loss-of-function effects on both KCNQ1- and KCNH2-encoded channel currents.Conclusions The KCNE1-D85N polymorphism was significantly more frequent in our LQTS probands. The functional variant is a disease-causing gene variant of LQTS phenotype that functions by interacting with KCNH2 and KCNQ1. Since its allele frequency was similar to 1% among control individuals, KCNE1-D85N may be a clinically important genetic variant. (J Am Coll Cardiol 2009; 54: 812-9) (C) 2009 by the American College of Cardiology Foundation