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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
biochemistry, genetics and molecular biology
High prevalence of long QT syndrome-associated SCN5A variants in patients with early-onset lone atrial fibrillation
Circulation: Cardiovascular Genetics, Volume 5, No. 4, Year 2012
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Description
Background: Atrial fibrillation (AF) is the most common cardiac arrhythmia. The cardiac sodium channel, NaV1.5, 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. © 2012 American Heart Association, Inc.
Authors & Co-Authors
Olesen, Morten Salling
Denmark, Copenhagen
Københavns Universitet
Denmark, Copenhagen
Statens Serum Institut
Denmark, Copenhagen
Rigshospitalet
Yuan, Lei
Denmark, Copenhagen
Københavns Universitet
Denmark, Copenhagen
Statens Serum Institut
Liang, Bo
Denmark, Copenhagen
Københavns Universitet
Denmark, Copenhagen
Statens Serum Institut
Nielsen, Jonas Bille
Denmark, Copenhagen
Københavns Universitet
Denmark, Copenhagen
Statens Serum Institut
Denmark, Copenhagen
Rigshospitalet
Hedley, P. L.
Denmark, Copenhagen
Statens Serum Institut
Christiansen, Michael
Denmark, Copenhagen
Statens Serum Institut
Haunsø, Stig
Denmark, Copenhagen
Københavns Universitet
Denmark, Copenhagen
Statens Serum Institut
Denmark, Copenhagen
Rigshospitalet
Jespersen, Thomas Sand
Denmark, Copenhagen
Københavns Universitet
Denmark, Copenhagen
Statens Serum Institut
Statistics
Citations: 131
Authors: 8
Affiliations: 3
Identifiers
Doi:
10.1161/CIRCGENETICS.111.962597
ISSN:
19423268
Research Areas
Genetics And Genomics
Noncommunicable Diseases
Study Design
Cross Sectional Study
Cohort Study