A novel SCN5A gain-of-function mutation M1875T associated with familial atrial fibrillation

JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY

卷:52

Article

Makiyama, Takeru¹  Akao, Masaharu¹  Shizuta, Satoshi¹  Doi, Takahiro¹  Nishiyama, Kei¹  Oka, Yuko²  Ohno, Seiko¹  Nishio, Yukiko¹  Tsuji, Keiko²  Itoh, Hideki²  Kimura, Takeshi¹  Kita, Toru¹  Horie, Minoru² 

[1] Kyoto Univ, Grad Sch Med, Dept Cardiovasc Med, Sakyo Ku, Kyoto 6068507, Japan

[2] Shiga Univ Med Sci, Dept Cardiovasc & Resp Med, Otsu, Shiga 52021, Japan

关键词: arrhythmia;    atrial fibrillation;    genetics;    ion channels;    sodium;   

DOI  :  10.1016/j.jacc.2008.07.013

来源: Elsevier

【 摘 要 】

Objectives This study describes a novel heterozygous gain- of- function mutation in the cardiac sodium (Na+) channel gene, SCN5A, identified in a Japanese family with lone atrial fibrillation (AF). Background SCN5A mutations have been associated with a variety of inherited arrhythmias, but the gain- of- function type modulation in SCN5A is associated with only 1 phenotype, long-QT syndrome type 3 (LQTS3). Methods We studied a Japanese family with autosomal dominant hereditary AF, multiple members of which showed an onset of AF or frequent premature atrial contractions at a young age. Results The 31- year- old proband received radiofrequency catheter ablation, during which time numerous ectopic firings and increased excitability throughout the right atrium were documented. Mutational analysis identified a novel missense mutation, M1875T, in SCN5A. Further investigations revealed the familial aggregation of this mutation in all of the affected individuals. Functional assays of the M1875T Na+ channels using a whole- cell patch- clamp demonstrated a distinct gain- of- function type modulation; a pronounced depolarized shift (+ 16.4 mV) in V-1/2 of the voltage dependence of steady- state inactivation; and no persistent Na+ current, which is a defining mechanism of LQTS3. These biophysical features of the mutant channels are potentially associated with increased atrial excitability and normal QT interval in all of the affected individuals. Conclusions We identified a novel SCN5A mutation associated with familial AF. The mutant channels displayed a gain- of- function type modulation of cardiac Na+ channels, which is a novel mechanism predisposing to increased atrial excitability and familial AF. This is a new phenotype resulting from the SCN5A gain-of-function mutations and is distinct from LQTS3.

【 授权许可】

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