Impact of Gain-of-Function Gene Variant of SCN1B T189M, on Occurrence of Lone Atrial Fibrillation

概要

論文の詳細を見る
Background: Mutations in multiple genes have been implicated in familial atrial fibrillation (AF), and recent report showed that loss-of-function mutations in SCN1B and SCN2B were associated with AF. Therefore, we examined a cohort of patients with lone AF for variants in the sodium channel β-subunit genes. Methods and Results: In 74 patients (54 men, mean age 56 years) with lone AF, we screened for variants in all exons of SCN1B, SCN2B, and SCN3B. Onset of AF was 46±12 years old. There were 19 with famlial AF and 45 with paroxysmal AF. We identified a novel variant in SCN1B (T189M) from 2 unrelated patients with paroxysmal AF; one is homozygous carrier and the other is heterozygous carrier. Electrophysiological study of the Na+ channels in HEK293 cells showed the maximum peak current density for SCN1B T189M coexpressed with SCN5A was significantly bigger than that for wild type SCN1B. The voltage dependences of activation and steady-state inactivation of SCN1B T189M were both negatively shifted. Conclusions: These results demonstrate that T189M variant in sodium channel β1 subunit gene may predispose patients without underlying heart disease to increased atrial excitability and AF, providing new insights into the molecular etiology involved in the pathogenesis of AF.