Mutations in SCN10A Are Responsible for a Large Fraction of Cases of Brugada Syndrome

JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY

卷:64

Article

Hu, Dan¹  Barajas-Martinez, Hector¹  Pfeiffer, Ryan¹  Dezi, Fabio¹  Pfeiffer, Jenna¹  Buch, Tapan¹  Betzenhauser, Matthew J.¹  Belardinelli, Luiz²  Kahlig, Kristopher M.²  Rajamani, Sridharan²  DeAntonio, Harry J.³  Myerburg, Robert J.⁴  Ito, Hiroyuki⁵  Deshmukh, Pramod⁶  Marieb, Mark⁷  Nam, Gi-Byoung⁸  Bhatia, Atul⁹  Hasdemir, Can¹⁰  Haissaguerre, Michel¹¹  Veltmann, Christian¹²  Schimpf, Rainer¹³  Borggrefe, Martin¹³  Viskin, Sami¹⁴  Antzelevitch, Charles¹ 

[1] Masonic Med Res Lab, Utica, NY 13501 USA

[2] Gilead Sci, Fremont, CA USA

[3] E Carolina Univ, Brody Sch Med, East Carolina Heart Inst, Greenville, NC USA

[4] Univ Miami, Miller Sch Med, Miami, FL 33136 USA

[5] Showa Univ, Dept Cardiol, Tokyo, Japan

[6] Guthrie Clin, Sayre, PA USA

[7] Yale Univ, Sch Med, New Haven, CT USA

[8] Univ Ulsan, Coll Med, Asan Med Ctr, Dept Internal Med, Seoul, South Korea

[9] Aurora Cardiovasc Serv, Milwaukee, WI USA

[10] Ege Univ, Sch Med, Dept Cardiol, Izmir, Turkey

[11] Univ Bordeaux 2, Hosp Cardiol Haut Leveque, Pessac, France

[12] Hannover Med Sch, Dept Cardiol & Angiol, Hannover, Germany

[13] Univ Med Ctr Mannheim, German Ctr Cardiovasc Res, Mannheim, Germany

[14] Tel Aviv Univ, Sackler Sch Med, Tel Aviv Sourasky Med Ctr, Dept Cardiol, IL-69978 Tel Aviv, Israel

关键词: Brugada syndrome;    cardiac arrhythmias;    cardiac conduction disease;    electrophysiology;    genetics;    sudden cardiac death;   

DOI  :  10.1016/j.jacc.2014.04.032

来源: Elsevier

【 摘 要 】

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 Na(v)1.8, 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 Na(v)1.8 and Na(v)1.5 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. (C) 2014 by the American College of Cardiology Foundation.

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