Dan Roden
Faculty Member
Last active: 3/24/2020

Mutations in sodium channel β1- and β2-subunits associated with atrial fibrillation.

Watanabe H, Darbar D, Kaiser DW, Jiramongkolchai K, Chopra S, Donahue BS, Kannankeril PJ, Roden DM
Circ Arrhythm Electrophysiol. 2009 2 (3): 268-75

PMID: 19808477 · PMCID: PMC2727725 · DOI:10.1161/CIRCEP.108.779181

BACKGROUND - We and others have reported mutations in the cardiac predominant sodium channel gene SCN5A in patients with atrial fibrillation (AF). We also have reported that SCN1B is associated with Brugada syndrome and isolated cardiac conduction disease. We tested the hypothesis that mutations in the 4 sodium channel beta-subunit genes SCN1B-SCN4B contribute to AF susceptibility.

METHODS AND RESULTS - Screening for mutations in the 4 beta-subunit genes was performed in 480 patients with AF (118 patients with lone AF and 362 patients with AF and cardiovascular disease) and 548 control subjects (188 ethnically defined anonymized subjects and 360 subjects without AF). The effects of mutant beta-subunits on SCN5A mediated currents were studied using electrophysiological studies. We identified 2 nonsynonymous 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 control subjects. In 3 of 4 mutation carriers, the ECGs showed saddleback-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 beta1- or beta2-subunits reduced SCN5A-mediated current and altered channel gating compared with coexpression of wild-type subunits.

CONCLUSIONS - Loss of function mutations in sodium channel beta-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.

MeSH Terms (20)

Adult Animals Atrial Fibrillation CHO Cells Cricetinae Cricetulus Electrocardiography Female Genetic Predisposition to Disease Heterozygote Humans Male Middle Aged Mutation, Missense Phenotype Reverse Transcriptase Polymerase Chain Reaction Sodium Channels Structure-Activity Relationship Voltage-Gated Sodium Channel beta-1 Subunit Voltage-Gated Sodium Channel beta-4 Subunit

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