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(Circulation. 2007;116:II_54.)
© 2007 American Heart Association, Inc.

Na and Ca Channels in the Heart

Abstract 356: Loss of Function Mutations of Sodium Channel Beta-1 and Beta-2 Subunits Associated with Atrial Fibrillation and ST-segment Elevation

Hiroshi Watanabe; Dawood Darbar; Christiana R Ingram; Kim Jiramongkolchai; Sameer S Chopra; Gayle Kucera; Tanya Stubblefield; Janey Wang; Dan M Roden

Vanderbilt Univ, Nashville, TN

Background: We have recently reported mutations in the cardiac sodium channel gene SCN5A in 5.9% of patients with atrial fibrillation (AF). In this study, we tested the hypothesis that mutations in sodium channel ß subunit genes SCN1B-4B contribute to AF susceptibility.

Methods and results: All 4 ßsubunit genes were resequenced in 376 patients with AF (118 patients with lone AF and 258 patients with AF and cardiovascular disease) and 188 ethnically-defined controls. 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, there was saddle back type ST-segment elevation in the right precordial leads of electrocardiogram. Transcripts encoding both SCN1B and SCN2B were detected in human atrium and ventricle. To assess function in vitro, CHO cells were transfected with SCN5A without ß subunit, SCN5A with wild-type (WT) ß subunit, or SCN5A with mutant ß subunit: all 4 mutants altered SCN5A current to a variable extent compared to WT ß subunits. WT ß1 increased SCN5A currents by 75%, and induced a negative shift in steady-state activation (–10.2 mV) and inactivation (–6.7 mV), compared to SCN5A alone. D153N ß1 caused partial loss of function, with increased SCN5A current but to a smaller extent (24%) than WT ß1, and a negative shift in steady-state activation (–12.1 mV) and inactivation (–8.1 mV) similar to WT. R85H ß1 produced a pure loss of function, with currents no different from SCN5A alone. WT ß2 did not change SCN5A current amplitude, while R28Q ß2 and R28W ß2 decreased current by 36% and 30%, respectively; and positively shifted steady-state activation by +7.4 mV and +5.1 mV, respectively, compared to WT.

Conclusion: Loss of function mutations in sodium channel ß 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.

This Article Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Watanabe, H. Articles by Roden, D. M PubMed Articles by Watanabe, H. Articles by Roden, D. M