Identification of a novel missense SCN5A mutation in a Chinese Han family with Brugada syndrome

Abstract

Brugada syndrome is an inherited cardiac arrythmia causes sudden death usually associated with loss-of-function mutations of SCN5A, a gene encodes α subunit of cardiac sodium channel Nav1.5 which plays key role in cardiac function. SCN5A mutation screen is often applied to diagnosis of Brugada syndrome, while its genetic etiology remains not fully understood. In present study, we performed sequence analysis of SCN5A gene in a Chinese Han family with Brugada syndrome, and found a novel heterozygous mutation (c.4969 C > T, p.Leu1657Phe). Functional electrophysiological study showed that the mutation reduced ∼60% sodium current density and largely reduced Nav1.5 activation (positively shifted activation curve by 13.93 mV), which are the key features for the pathogenesis of Brugada syndrome. However, the mutation enhanced Nav1.5 function as it slightly decreased inactivation (positively shifted inactivation curve by 7.4 mV) and accelerated recovery (decreased fast recovery by 1.39 ms). In addition, the mutation acts in a dominant negatively manner as it reduced ∼49% sodium current densities in heterozygous state. In conclusion, the study describes a novel SCN5A mutation of p.Leu1657Phe associated with Brugada syndrome, the mutation reduced current density in a dominant negative manner and altered gating kinetics, which will benefit early clinical diagnosis of Brugada syndrome.