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CLINICAL RESEARCH: HEART RHYTHM DISORDER

A Novel SCN5A Gain-of-Function Mutation M1875T Associated With Familial Atrial Fibrillation

Takeru Makiyama, MD, PhD^_*, Masaharu Akao, MD, PhD^_*,_*, Satoshi Shizuta, MD^_*, Takahiro Doi, MD^_*, Kei Nishiyama, MD^_*, Yuko Oka, MD, Seiko Ohno, MD, PhD^_*, Yukiko Nishio, MD^_*, Keiko Tsuji, MS, Hideki Itoh, MD, PhD, Takeshi Kimura, MD, PhD^_*, Toru Kita, MD, PhD^_* and Minoru Horie, MD, PhD

^_* Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan
Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Otsu, Japan

Manuscript received March 3, 2008; revised manuscript received July 7, 2008, accepted July 10, 2008.

^_* Reprint requests and correspondence: Dr. Masaharu Akao, Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan (Email: akao{at}kuhp.kyoto-u.ac.jp).

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.

Key Words: arrhythmia • atrial fibrillation • genetics • ion channels • sodium

Abbreviations and Acronyms   AF = atrial fibrillation   AT = atrial tachycardia   ECG = electrocardiogram   LQTS3 = long-QT syndrome type 3   PAC = premature atrial contraction   WT = wild-type

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J. Am. Coll. Cardiol. 2008 52: A31. [Full Text] [PDF]