%0 Case Reports
%T Characterization of a novel SCN5A genetic variant A1294G associated with mixed clinical phenotype.
%A Zaytseva AK
%A Karpushev AV
%A Kiselev AM
%A Mikhaylov EN
%A Lebedev DS
%A Zhorov BS
%A Kostareva AA
%J Biochem Biophys Res Commun
%V 516
%N 3
%D 08 2019 27
%M 31253402
%F 3.322
%R 10.1016/j.bbrc.2019.06.080
%X 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.