Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Japan.
Circ Arrhythm Electrophysiol. 2011 Jun;4(3):352-61. doi: 10.1161/CIRCEP.110.959619. Epub 2011 Apr 14.
Brugada syndrome (BrS) has a significantly higher incidence among the male sex. Among genes coding ion channels and their modulatory proteins, KCNE5 (KCNE1L) is located in the X chromosome and encodes an auxiliary β-subunit for K channels. KCNE5 has been shown to modify the transient outward current (I(to)), which plays a key role in determining the repolarization process in the myocardium. This study investigated whether KCNE5 mutations could be responsible for BrS and other idiopathic ventricular fibrillation (IVF).
In 205 Japanese patients with BrS or IVF who tested negative for SCN5A mutation, we conducted a genetic screen for KCNE5 variants. We identified 2 novel KCNE5 variants: p.Y81H in 3 probands and p.[D92E;E93X] in 1 proband from 4 unrelated families. Y81H was identified in 1 man and 2 women; D92E;E93X was found in a 59-year-old man. All probands received implantable cardioverter-defibrillators. Functional consequences of the KCNE5 variants were determined through biophysical assay using cotransfection with KCND3 or KCNQ1. In the experiments with KCND3, which encodes Kv4.3, I(to) was significantly increased for both KCNE5 variants compared to wild type. In contrast, there were no significant changes in current properties reconstructed by KCNQ1+ wild type KCNE5 and the 2 variants. With the simulation model, both variants demonstrated notch-and-dome or loss-of-dome patterns.
KCNE5 modulates I(to), and its novel variants appeared to cause IVF, especially BrS, in male patients through gain-of-function effects on I(to). Screening for KCNE5 variants is relevant for BrS or IVF.
Brugada 综合征（BrS）在男性中发病率明显较高。在编码离子通道及其调节蛋白的基因中，KCNE5（KCNE1L）位于 X 染色体上，编码 K 通道的辅助β亚基。已经表明 KCNE5 可以调节瞬时外向电流（I(to)），这在决定心肌复极化过程中起着关键作用。本研究探讨了 KCNE5 突变是否与 BrS 和其他特发性心室颤动（IVF）有关。
在 205 名经 SCN5A 突变检测呈阴性的 BrS 或 IVF 的日本患者中，我们对 KCNE5 变体进行了基因筛查。我们发现了 2 种新的 KCNE5 变体：3 个先证者中有 p.Y81H，1 个先证者中有 p.[D92E；E93X]，来自 4 个无关的家族。Y81H 发现于 1 名男性和 2 名女性；D92E；E93X 发现于 1 名 59 岁男性。所有先证者均接受了植入式心脏复律除颤器。通过与 KCND3 或 KCNQ1 共转染进行生物物理测定，确定了 KCNE5 变体的功能后果。在 KCND3 的实验中，与野生型相比，两种 KCNE5 变体的 I(to) 均显著增加。相反，KCNQ1+野生型 KCNE5 和 2 种变体重建的电流特性没有明显变化。通过仿真模型，两种变体均表现出 Notch-and-Dome 或 Dome-loss 模式。
KCNE5 调节 I(to)，其新型变体似乎通过对 I(to)的功能获得性作用导致男性患者发生 IVF，尤其是 BrS。筛查 KCNE5 变体与 BrS 或 IVF 相关。
