Characterization of a novel SCN5A genetic variant A1294G associated with mixed clinical phenotype

Mutations in gene SCN5A, which encodes cardiac voltage-gated sodium channel Na_v1.5, are associated with multiple clinical phenotypes. Here we describe a novel A1294G genetic variant detected in a male patient with combined clinical phenotype including atrioventricular II block, Brugada-like ECG, septal fibrosis, right ventricular dilatation and decreased left ventricular contractility. Residue A1294 is located in the IIIS3-S4 extracellular loop, in proximity to several residues whose mutations are associated with sodium channelopathies. The wild-type channel Na_v1.5 and mutant Na_v1.5-A1294G were expressed in the CHO-K1 and HEK293T cells and whole-cell sodium currents were recorded using the patch-clamp method. The A1294G channels demonstrated a negative shift of steady-state inactivation, accelerated fast and slow inactivation and decelerated recovery from intermediate inactivation. Our study reveals biophysical mechanism of the Na_v1.5-A1294G dysfunction, which may underlie the combined phenotypic manifestation observed in the patient.