Heart Institute, Sheba Medical Center, Tel Hashomer, Israel Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
J Cardiovasc Electrophysiol. 2010 Dec;21(12):1365-72. doi: 10.1111/j.1540-8167.2010.01844.x.
to conduct a clinical, genetic, and functional analysis of 3 unrelated families with familial sinus bradycardia (FSB).
mutations in the hyperpolarization-activated nucleotide-gated channel (HCN4) are known to be associated with FSB.
three males of Moroccan Jewish descent were hospitalized: 1 survived an out-of-hospital cardiac arrest and 2 presented with weakness and presyncopal events. All 3 had significant sinus bradycardia, also found in other first-degree relatives, with a segregation suggesting autosomal-dominant inheritance. All had normal response to exercise and normal heart structure. Sequencing of the HCN4 gene in all patients revealed a C to T transition at nucleotide position 1,454, which resulted in an alanine to valine change (A485V) in the ion channel pore found in most of their bradycardiac relatives, but not in 150 controls. Functional expression of the mutated ion channel in Xenopus oocytes and in human embryonic kidney 293 cells revealed profoundly reduced function and synthesis of the mutant channel compared to wild-type.
we describe a new mutation in the HCN4 gene causing symptomatic FSB in 3 unrelated individuals of similar ethnic background that may indicate unexplained FSB in this ethnic group. This profound functional defect is consistent with the symptomatic phenotype.
对 3 个无血缘关系的家族性窦性心动过缓（FSB）患者进行临床、遗传和功能分析。
现已发现，超极化激活的核苷酸门控通道（HCN4）突变与 FSB 相关。
3 名摩洛哥裔犹太男性住院：1 人经历院外心脏骤停存活，2 人出现虚弱和晕厥前事件。3 人均存在显著窦性心动过缓，该疾病也存在于其他一级亲属中，表明常染色体显性遗传。所有患者对运动的反应均正常，心脏结构正常。对所有患者的 HCN4 基因进行测序，发现第 1454 位核苷酸的 C 到 T 转换，导致离子通道孔中的丙氨酸到缬氨酸改变（A485V），这种改变在大多数心动过缓的亲属中存在，但在 150 名对照者中不存在。突变离子通道在非洲爪蟾卵母细胞和人胚肾 293 细胞中的功能表达显示，与野生型相比，突变通道的功能和合成明显降低。
我们描述了 HCN4 基因的一个新突变，导致 3 个无血缘关系的、具有相似种族背景的个体出现有症状的 FSB，这可能表明该种族群体中存在不明原因的 FSB。这种明显的功能缺陷与有症状的表型一致。
