A novel gain-of-function mutation SCN5A-N470K associated with African American familial atrial fibrillation

The cardiac sodium channel Nav1.5, encoded by the SCN5A gene, is crucial for the generation and propagation of cardiac action potential. While SCN5A mutations have been linked to familial atrial fibrillation (AF), the functional impact of certain mutations remains unclear. This study aims to identify new SCN5A mutation associated with AF and investigate the mechanism of the mutation dysregulation of SCN5A channel function underlying AF.

We identified a three-generation African American family with a history of familial AF. Functional characterization of an SCN5A mutation was performed using whole-cell patch-clamp recordings in HEK cells expressing the recombinant mutant channels.

The proband, along with his mother and maternal grandmother, all presented with early-onset symptomatic paroxysmal AF, which co-segregated with the SCN5A-N470K mutation. The N470K mutation exhibited different electrophysiological properties when compared to the wild-type channel. Functional evaluation of the SCN5A-N470K variant revealed an increased peak sodium current, a hyperpolarizing shift in the voltage-dependence of steady-state activation, and a depolarizing shift in voltage-dependent inactivation. Additionally, N470K mutation did not produce significantly larger persistent current.

The SCN5A-N470K mutation represents a gain-of-function alteration characterized by increased peak sodium current, and enhanced window current defined by the overlap of voltage-dependent inactivation and activation curves. These changes may alter myocardial excitability or conduction, providing a plausible mechanism by which the SCN5A-N470K mutation increases susceptibility to AF in this African American family.