{Reference Type}: Case Reports
{Title}: Characterization of a novel SCN5A genetic variant A1294G associated with mixed clinical phenotype.
{Author}: Zaytseva AK;Karpushev AV;Kiselev AM;Mikhaylov EN;Lebedev DS;Zhorov BS;Kostareva AA;
{Journal}: Biochem Biophys Res Commun
{Volume}: 516
{Issue}: 3
{Year}: 08 2019 27
{Factor}: 3.322
{DOI}: 10.1016/j.bbrc.2019.06.080
{Abstract}: Mutations in gene SCN5A, which encodes cardiac voltage-gated sodium channel Nav1.5, 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 Nav1.5 and mutant Nav1.5-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 Nav1.5-A1294G dysfunction, which may underlie the combined phenotypic manifestation observed in the patient.