Abstract 1523: A Novel SCN5A Gain-of-Function Mutation M1875T Associated with Familial Atrial Fibrillation
Background: Mutations in the cardiac sodium (Na+) channel gene, SCN5A, have been associated with a variety of inherited arrhythmias, but the gain-of-function type modulation in SCN5A is associated with only one phenotype, long-QT syndrome type3 (LQTS3).
Methods and Results: We studied a Japanese family with autosomal dominant hereditary atrial fibrillation (AF), multiple members of which showed onset of AF or frequent premature atrial contractions at a young age. The 31-year-old proband received radio-frequency 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 aggregation of this mutation in all of the affected individuals (Figure A⇓). Functional assays of the M1875T Na+ channels using whole-cell patch-clamp demonstrated a distinct gain-of-function type modulation; a pronounced depolarized shift (+16.4 mV) in V1/2 of the voltage dependence of steady-state inactivation (Figure B⇓), and no late 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 increased atrial excitability and familial AF. This is a new phenotype resulting from the SCN5A gain-of-function mutations and is distinct from LQTS3.