The Danish National Research Foundation Centre for Cardiac Arrhythmia, Copenhagen, Denmark.
BMC Med Genet. 2012 Apr 3;13:24. doi: 10.1186/1471-2350-13-24.
Atrial fibrillation (AF) is the most common arrhythmia. The potassium current IKs is essential for cardiac repolarization. Gain-of-function mutations in KV7.1, the pore-forming α-subunit of the IKs channel, have been associated with AF. We hypothesized that early-onset lone AF is associated with mutations in the IKs channel regulatory subunit KCNE1.
In 209 unrelated early-onset lone AF patients (< 40 years) the entire coding sequence of KCNE1 was bidirectionally sequenced. We analyzed the identified KCNE1 mutants electrophysiologically in heterologous expression systems.
Two non-synonymous mutations G25V and G60D were found in KCNE1 that were not present in the control group (n = 432 alleles) and that have not previously been reported in any publicly available databases or in the exom variant server holding exom data from more than 10.000 alleles. Proband 1 (female, age 45, G25V) had onset of paroxysmal AF at the age of 39 years. Proband 2 (G60D) was diagnosed with lone AF at the age of 33 years. The patient has inherited the mutation from his mother, who also has AF. Both probands had no mutations in genes previously associated with AF. In heterologous expression systems, both mutants showed significant gain-of-function for IKs both with respect to steady-state current levels, kinetic parameters, and heart rate-dependent modulation.
Mutations in KV7.1 leading to gain-of-function of IKs current have previously been described in lone AF, yet this is the first time a mutation in the beta-subunit KCNE1 is associated with the disease. This finding further supports the hypothesis that increased potassium current enhances AF susceptibility.
心房颤动（AF）是最常见的心律失常。钾电流 IKs 对心脏复极至关重要。IKs 通道的孔形成α亚基 KV7.1 的功能获得性突变与 AF 有关。我们假设早发性孤立性 AF 与 IKs 通道调节亚基 KCNE1 的突变有关。
在 209 名无关的早发性孤立性 AF 患者（<40 岁）中，对 KCNE1 的整个编码序列进行了双向测序。我们在异源表达系统中分析了鉴定出的 KCNE1 突变体的电生理特性。
在 KCNE1 中发现了两个非同义突变 G25V 和 G60D，它们在对照组（n=432 个等位基因）中不存在，也没有在任何公开可用的数据库或 exom 变体服务器中报告，该服务器包含来自 10000 多个等位基因的 exom 数据。先证者 1（女性，45 岁，G25V）在 39 岁时出现阵发性 AF。先证者 2（G60D）在 33 岁时被诊断为孤立性 AF。患者从其患有 AF 的母亲那里遗传了该突变。两名先证者在以前与 AF 相关的基因中均无突变。在异源表达系统中，两种突变体的 IKs 稳态电流水平、动力学参数和心率依赖性调节均表现出明显的功能获得。
以前在孤立性 AF 中描述了导致 IKs 电流功能获得的 KV7.1 突变，但这是首次报道β亚基 KCNE1 的突变与该疾病相关。这一发现进一步支持了增加钾电流增强 AF 易感性的假说。
