期刊
JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
卷 57, 期 21, 页码 2160-2168出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.jacc.2010.09.084
关键词
arrhythmia; dilated cardiomyopathy; genetics; ion channels
资金
- NIH/NHLBI [1 RO1 HL69071]
- NIH [MO1 RR00051-1575]
- American Heart Association [0150453N, 0250271N]
- Muscular Dystrophy Association [PN0007-056]
Objectives The aim of this study was to discern the role of the cardiac voltage-gated sodium ion channel SCN5A in the etiology of dilated cardiomyopathy (DCM). Background Dilated cardiomyopathy associates with mutations in the SCN5A gene, but the frequency, phenotype, and causative nature of these associations remain the focus of ongoing investigation. Methods Since 1991, DCM probands and family members have been enrolled in the Familial Cardiomyopathy Registry and extensively evaluated by clinical phenotype. Genomic deoxyribonucleic acid samples from 338 individuals among 289 DCM families were obtained and screened for SCN5A mutations by denaturing high-performance liquid chromatography and sequence analysis. Results We identified 5 missense SCN5A mutations among our DCM families, including novel mutations E446K, F1520L, and V1279I, as well as previously reported mutations D1275N and R222Q. Of 15 SCN5A mutation carriers in our study, 14 (93%) manifested arrhythmia: supraventricular arrhythmia (13 of 15), including sick sinus syndrome (5 of 15) and atrial fibrillation (9 of 15), ventricular tachycardia (5 of 15), and conduction disease (9 of 15). Conclusions Mutations in SCN5A were detected in 1.7% of DCM families. Two-thirds (6 of 9) of all reported DCM mutations in SCN5A localize to the highly conserved homologous S3 and S4 transmembrane segments, suggesting a shared mechanism of disruption of the voltage-sensing mechanism of this channel leading to DCM. Not surprisingly, SCN5A mutation carriers show a strong arrhythmic pattern that has clinical and diagnostic implications. (J Am Coll Cardiol 2011; 57: 2160-8) (C) 2011 by the American College of Cardiology Foundation
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