Department of Cardiology, Tongji Hospital, Tongji University School of Medicine, Shanghai, China.
J Hum Genet. 2009 May;54(5):277-83. doi: 10.1038/jhg.2009.26. Epub 2009 Apr 3.
Accumulating evidence reveals that genetic variants play pivotal roles in familial atrial fibrillation (AF). However, the molecular defects in most patients with AF remain to be identified. Here, we report on three novel KCNA5 mutations that were identified in 4 of 120 unrelated AF families. Among them, T527M was found in two AF families, and A576V and E610K in two other AF families, respectively. The mutations T527M and A576V were also detected in 2 and 1 of 256 patients with idiopathic AF, respectively. The same mutations were not observed in 200 secondary AF patients and 500 controls. Functional analyses revealed consistent loss-of-function effects of mutant KCNA5 proteins on the ultrarapidly activating delayed rectifier potassium currents. These findings expand the spectrum of mutations in KCNA5 linked to AF and provide new insight into the molecular mechanism involved in AF.
越来越多的证据表明，遗传变异在家族性心房颤动（AF）中起着关键作用。然而，大多数 AF 患者的分子缺陷仍有待确定。在这里，我们报告了在 120 个无关的 AF 家族中的 4 个家族中发现的 3 个新的 KCNA5 突变。其中，T527M 存在于两个 AF 家族中，A576V 和 E610K 分别存在于另外两个 AF 家族中。突变 T527M 和 A576V 也分别在 256 名特发性 AF 患者和 200 名继发性 AF 患者及 500 名对照中被检测到。在 200 名继发性 AF 患者和 500 名对照中未观察到相同的突变。功能分析显示突变 KCNA5 蛋白对超快激活延迟整流钾电流的一致失活作用。这些发现扩展了与 AF 相关的 KCNA5 突变谱，并为 AF 涉及的分子机制提供了新的见解。
