期刊
CIRCULATION-CARDIOVASCULAR GENETICS
卷 5, 期 4, 页码 450-459出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCGENETICS.111.962597
关键词
atrial fibrillation; genes; long-QT syndrome; QT interval electrocardiography; SCN5A
资金
- Danish Heart Foundation [07-10-R60-A1815-B573-22398, 11-04-R84-A3333-22660]
- John and Birthe Meyer Foundation
- Lundbeck Foundation
- Carlsberg Foundation
- Research Foundation of the Heart Centre Rigshospitalet
- Arvid Nilsson Foundation
- Director Ib Henriksens Foundation
- Kong Christian Foundation
- National Association for the Control of Circulatory Diseases,
- Aase and Ejnar Danielsen's Foundation
- stock brokers Henry Hansen and wife Karla Hansen
- Born Westergaard's Grant
- Kurt Bonnelycke and wife Mrs. Grethe Bonnelycke Foundation
Background-Atrial fibrillation (AF) is the most common cardiac arrhythmia. The cardiac sodium channel, Na(v)1.5, plays a pivotal role in setting the conduction velocity and the initial depolarization of the cardiac myocytes. We hypothesized that early-onset lone AF was associated with genetic variation in SCN5A. Methods and Results-The coding sequence of SCN5A was sequenced in 192 patients with early-onset lone AF. Eight nonsynonymous mutations (T220I, R340Q, T1304M, F1596I, R1626H, D1819N, R1897W, and V1951M) and 2 rare variants (S216L in 2 patients and F2004L) were identified. Of 11 genopositive probands, 6 (3.2% of the total population) had a variant previously associated with long QT syndrome type 3 (LQTS3). The prevalence of LQTS3-associated variants in the patients with lone AF was much higher than expected, compared with the prevalence in recent exome data (minor allele frequency, 1.6% versus 0.3%; P=0.003), mainly representing the general population. The functional effects of the mutations were analyzed by whole cell patch clamp in HEK293 cells; for 5 of the mutations previously associated with LQTS3, patch-clamp experiments showed an increased sustained sodium current, suggesting a mechanistic overlap between LQTS3 and early-onset lone AF. In 9 of 10 identified mutations and rare variants, we observed compromised biophysical properties affecting the transient peak current. Conclusions-In a cohort of patients with early-onset lone AF, we identified a high prevalence of SCN5A mutations previously associated with LQTS3. Functional investigations of the mutations revealed both compromised transient peak current and increased sustained current. (Circ Cardiovasc Genet. 2012;5:450-459.)
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据