on March 6, 2009
Published online before print March 6, 2009, doi: 10.1161/CIRCEP.108.779181
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Original Article |
Mutations in Sodium Channel Beta1 and Beta2 Subunits associated with Atrial Fibrillation.
Vanderbilt University
1 E-mail: dan.roden{at}vanderbilt.edu
Background—We and others have reported mutations in the cardiac predominant sodium channel gene SCN5A in patients with AF. We also have reported that SCN1B is associated with Brugada syndrome and isolated cardiac conduction disease. Here we tested the hypothesis that mutations in the 4 sodium channel β-subunit genes SCN1B - SCN4B contribute to atrial fibrillation (AF) susceptibility.
Methods and Results—Screening for mutations in the 4 β-subunit genes was performed in 480 patients with AF (118 patients with lone AF and 362 patients with AF and cardiovascular disease) and 548 controls (188 ethnically-defined anonymized subjects and 360 subjects without AF). The effects of mutant β-subunits on SCN5A mediated currents were studied using electrophysiological studies. We identified 2 non-synonymous variants in SCN1B (resulting in R85H, D153N) and 2 in SCN2B (R28Q, R28W) in patients with AF. These occur at residues highly conserved across mammals, and were absent in controls. In 3 of 4 mutation carriers, the electrocardiograms showed saddle back type ST-segment elevation in the right precordial leads. Transcripts encoding both SCN1B and SCN2B were detected in human atrium and ventricle. In heterologous expression studies using Chinese hamster ovary cells, the mutant β1- or β2-subunits reduced SCN5A mediated current and altered channel gating compared to coexpression of wild-type subunits.
Conclusions—Loss of function mutations in sodium channel β-subunits were identified in patients with AF, and were associated with a distinctive ECG phenotype. These findings further support the hypothesis that decreased sodium current enhances AF susceptibility.
Key Words: arrhythmia • genetics • ion channels • mutations • sodium channel
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