Referenced in: none

Automatically associated channels: Nav1.5

Title: Sodium channelopathy underlying familial sick sinus syndrome with early onset and predominantly male characteristics.

Authors: Keisuke Abe, Taku Machida, Naokata Sumitomo, Hirokazu Yamamoto, Kimie Ohkubo, Ichiro Watanabe, Takeru Makiyama, Satoki Fukae, Masaki Kohno, Daniel T Harrell, Taisuke Ishikawa, Yukiomi Tsuji, Akihiko Nogami, Taichi Watabe, Yasushi Oginosawa, Haruhiko Abe, Koji Maemura, Hideki Motomura, Naomasa Makita

Journal, date & volume: Circ Arrhythm Electrophysiol, 2014 Jun , 7, 511-7

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/24762805

Abstract
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.