@article{oai:nagasaki-u.repo.nii.ac.jp:00005687,
 author = {Abe, Keisuke and Machida, Taku and Sumitomo, Naokata and Yamamoto, Hirokazu and Ohkubo, Kimie and Watanabe, Ichiro and Makiyama, Takeru and Fukae, Satoki and Kohno, Masaki and Harrell, Daniel T. and Ishikawa, Taisuke and Tsuji, Yukiomi and Nogami, Akihiko and Watabe, Taichi and Oginosawa, Yasushi and Abe, Haruhiko and Maemura, Koji and Motomura, Hideki and Makita, Naomasa},
 issue = {3},
 journal = {Circulation: Arrhythmia and Electrophysiology},
 month = {Jun},
 note = {Background-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 identifcation of causative genes, including cardiac Na channel (SCN5A), the pathogenesis and molecular epidemiology of familial SSS remain undetermined primarily because of its rarity. Methods and Results-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 identifed 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 signifcantly 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). Conclusions-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., Circulation: Arrhythmia and Electrophysiology, 7(3), pp.511-517; 2014},
 pages = {511--517},
 title = {Sodium Channelopathy Underlying Familial Sick Sinus Syndrome With Early Onset and Predominantly Male Characteristics},
 volume = {7},
 year = {2014}
}