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ABSTRACT: Background
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.Objectives
The purpose of this study was to test the hypothesis that SCN10A variants contribute to the development of Brugada syndrome (BrS).Methods
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.Results
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.Conclusions
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.
SUBMITTER: Hu D
PROVIDER: S-EPMC4116276 | biostudies-literature | 2014 Jul
REPOSITORIES: biostudies-literature
Hu Dan D Barajas-Martínez Hector H Pfeiffer Ryan R Dezi Fabio F Pfeiffer Jenna J Buch Tapan T Betzenhauser Matthew J MJ Belardinelli Luiz L Kahlig Kristopher M KM Rajamani Sridharan S DeAntonio Harry J HJ Myerburg Robert J RJ Ito Hiroyuki H Deshmukh Pramod P Marieb Mark M Nam Gi-Byoung GB Bhatia Atul A Hasdemir Can C Haïssaguerre Michel M Veltmann Christian C Schimpf Rainer R Borggrefe Martin M Viskin Sami S Antzelevitch Charles C
Journal of the American College of Cardiology 20140701 1
<h4>Background</h4>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.<h4>Objectives</h4>The purpose of this study was to test the hypothesis that SCN10A variants contribute to the development of Brugada syndrome (BrS).<h4>Methods</h4>Clinical analysis and direct sequencing of BrS susceptibili ...[more]