Referenced in: none

Automatically associated channels: Nav1.5 , Nav1.8

Title: Mutations in SCN10A are responsible for a large fraction of cases of Brugada syndrome.

Authors: Dan Hu, Hector Barajas-Martinez, Ryan Pfeiffer, Fabio Dezi, Jenna Pfeiffer, Tapan Buch, Matthew J Betzenhauser, Luiz Belardinelli, Kristopher M Kahlig, Sridharan Rajamani, Harry J DeAntonio, Robert J Myerburg, Hiroyuki Ito, Pramod Deshmukh, Mark Marieb, Gi-Byoung Nam, Atul Bhatia, Can Hasdemir, Michel Haïssaguerre, Christian Veltmann, Rainer Schimpf, Martin Borggrefe, Sami Viskin, Charles Antzelevitch

Journal, date & volume: J. Am. Coll. Cardiol., 2014 Jul 8 , 64, 66-79

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/24998131

Abstract
BrS is an inherited sudden cardiac death syndrome. Less than 35% of BrS probands have genetically identified pathogenic variants. Recent evidence has implicated SCN10A, a neuronal sodium channel gene encoding Nav1.8, in the electrical function of the heart.The purpose of this study was to test the hypothesis that SCN10A variants contribute to the development of Brugada syndrome (BrS).Clinical analysis and direct sequencing of BrS susceptibility genes were performed for 150 probands and family members as well as >200 healthy controls. Expression and coimmunoprecipitation studies were performed to functionally characterize the putative pathogenic mutations.We identified 17 SCN10A mutations in 25 probands (20 male and 5 female); 23 of the 25 probands (92.0%) displayed overlapping phenotypes. SCN10A mutations were found in 16.7% of BrS probands, approaching our yield for SCN5A mutations (20.1%). Patients with BrS who had SCN10A mutations were more symptomatic and displayed significantly longer PR and QRS intervals compared with SCN10A-negative BrS probands. The majority of mutations localized to the transmembrane-spanning regions. Heterologous coexpression of wild-type (WT) SCN10A with WT-SCN5A in HEK cells caused a near doubling of sodium channel current compared with WT-SCN5A alone. In contrast, coexpression of SCN10A mutants (R14L and R1268Q) with WT-SCN5A caused a 79.4% and 84.4% reduction in sodium channel current, respectively. The coimmunoprecipitation studies provided evidence for the coassociation of Nav1.8 and Nav1.5 in the plasma membrane.Our study identified SCN10A as a major susceptibility gene for BrS, thus greatly enhancing our ability to genotype and risk stratify probands and family members.