Referenced in: none

Automatically associated channels: Kv7.1 , Nav1.5

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

Authors: Takeru Makiyama, Masaharu Akao, Satoshi Shizuta, Takahiro Doi, Kei Nishiyama, Yuko Oka, Seiko Ohno, Yukiko Nishio, Keiko Tsuji, Hideki Itoh, Takeshi Kimura, Toru Kita, Minoru Horie

Journal, date & volume: J. Am. Coll. Cardiol., 2008 Oct 14 , 52, 1326-34

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/18929244

Abstract
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).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).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.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.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.