SCN5A Variants: Association With Cardiac Disorders

Abstract

The SCN5A gene encodes the alpha subunit of the main cardiac sodium channel Na_v1.5. This channel predominates inward sodium current (INa) and plays a critical role in regulation of cardiac electrophysiological function. Since 1995, SCN5A variants have been found to be causatively associated with Brugada syndrome, long QT syndrome, cardiac conduction system dysfunction, dilated cardiomyopathy, etc. Previous genetic, electrophysiological, and molecular studies have identified the arrhythmic and cardiac structural characteristics induced by SCN5A variants. However, due to the variation of disease manifestations and genetic background, impact of environmental factors, as well as the presence of mixed phenotypes, the detailed and individualized physiological mechanisms in various SCN5A-related syndromes are not fully elucidated. This review summarizes the current knowledge of SCN5A genetic variations in different SCN5A-related cardiac disorders and the newly developed therapy strategies potentially useful to prevent and treat these disorders in clinical setting.

Keywords: Nav1.5; SCN5A; cardiac disorders; cardiac sodium channelopathy; therapeutic potential.

Figure 1

Na_v1.5 protein structure and some typical variants associated with gain- or loss- of the sodium channel function. Na_v1.5 is a large transmembrane protein with four internally homologous domains (DI-DIV), each containing six spanning segments (S1–S6) which are indicated by numbered cylinders. The four domains are interconnected by intracellular peptide chains, with N-terminal and C-end both located in the intracellular side. S4 segment works as a critical voltage-sensor because of its ample positive charge residues; S5 and S6 segments are lined by extracellular loops (P-loops) which are considered to determine the ion selectivity of the channel (S4 segments are depicted in yellow while the rest segments being blue). The transmembrane segment resembles one of the beta-subunits, which is depicted in purple. The location of the gain-of-function SCN5A variants are shown in blue circle while location of the loss-of-function SCN5A variants are shown in red rhombus.