From the Departments of Molecular Physiology (K.A., T.M., D.T.H., T.I., Y.T., N.M.), Pediatrics (H.Y., H.M.), and Cardiovascular Medicine (S.F., M.K., K.M.), Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; Departments of Pediatrics (N.S.) and Cardiovascular Medicine (K.O., I.W.), Nihon University Graduate School of Medicine, Tokyo, Japan; Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan (T.M.); Division of Heart Rhythm Management, Yokohama Rosai Hospital, Yokohama, Japan (A.N.); and The Second Department of Internal Medicine (T.W., Y.O.) and Department of Heart Rhythm Management (H.A.), University of Occupational and Environmental Health, Kitakyushu, Japan.
Circ Arrhythm Electrophysiol. 2014 Jun;7(3):511-7. doi: 10.1161/CIRCEP.113.001340. Epub 2014 Apr 24.
Sick sinus syndrome (SSS) is a common arrhythmia often associated with aging or organic heart diseases but may also occur in a familial form with a variable mode of inheritance. Despite the identification of causative genes, including cardiac Na channel (SCN5A), the pathogenesis and molecular epidemiology of familial SSS remain undetermined primarily because of its rarity.
We genetically screened 48 members of 15 SSS families for mutations in several candidate genes and determined the functional properties of mutant Na channels using whole-cell patch clamping. We identified 6 SCN5A mutations including a compound heterozygous mutation. Heterologously expressed mutant Na channels showed loss-of-function properties of reduced or no Na current density in conjunction with gating modulations. Among 19 family members with SCN5A mutations, QT prolongation and Brugada syndrome were associated in 4 and 2 individuals, respectively. Age of onset in probands carrying SCN5A mutations was significantly less (mean±SE, 12.4±4.6 years; n=5) than in SCN5A-negative probands (47.0±4.6 years; n=10; P<0.001) or nonfamilial SSS (74.3±0.4 years; n=538; P<0.001). Meta-analysis of SSS probands carrying SCN5A mutations (n=29) indicated profound male predominance (79.3%) resembling Brugada syndrome but with a considerably earlier age of onset (20.9±3.4 years).
The notable pathophysiological overlap between familial SSS and Na channelopathy indicates that familial SSS with SCN5A mutations may represent a subset of cardiac Na channelopathy with strong male predominance and early clinical manifestations.
病窦综合征（SSS）是一种常见的心律失常，常与衰老或器质性心脏病有关，但也可能以家族形式出现，具有不同的遗传方式。尽管已经确定了一些致病基因，包括心脏钠离子通道（SCN5A），但家族性 SSS 的发病机制和分子流行病学仍未确定，主要是因为其罕见。
我们对 15 个 SSS 家族的 48 名成员进行了几种候选基因的基因突变筛查，并使用全细胞膜片钳技术确定了突变钠离子通道的功能特性。我们发现了 6 种 SCN5A 突变，包括一种复合杂合突变。异源表达的突变钠离子通道表现出功能丧失的特性，即钠电流密度降低或消失，同时门控调节。在携带 SCN5A 突变的 19 名家族成员中，4 人伴有 QT 间期延长，2 人伴有 Brugada 综合征。携带 SCN5A 突变的先证者的发病年龄明显较小（平均±SE，12.4±4.6 岁；n=5），明显小于 SCN5A 阴性先证者（47.0±4.6 岁；n=10；P<0.001）或非家族性 SSS（74.3±0.4 岁；n=538；P<0.001）。携带 SCN5A 突变的 SSS 先证者（n=29）的荟萃分析表明，存在明显的男性优势（79.3%），类似于 Brugada 综合征，但发病年龄更早（20.9±3.4 岁）。
家族性 SSS 与钠离子通道病之间显著的病理生理学重叠表明，携带 SCN5A 突变的家族性 SSS 可能代表一种具有强烈男性优势和早期临床表现的心脏钠离子通道病亚群。
