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(Circulation. 2006;114:368-376.)
© 2006 American Heart Association, Inc.

Arrhythmia/Electrophysiology

SCN5A Polymorphism Restores Trafficking of a Brugada Syndrome Mutation on a Separate Gene

Steven Poelzing, PhD; Cinzia Forleo, MD, PhD; Melissa Samodell, BS; Lynn Dudash, BS; Sandro Sorrentino, PhD; Matteo Anaclerio, MD, PhD; Rossella Troccoli, MD; Massimo Iacoviello, MD; Roberta Romito, MD; Pietro Guida, MS; Mohamed Chahine, PhD; Mariavittoria Pitzalis, MD, PhD; Isabelle Deschênes, PhD

From the Heart and Vascular Research Center and Department of Medicine, MetroHealth Campus, Case Western Reserve University, Cleveland, Ohio (S.P., M.S., L.D., I.D.); Institute of Cardiology, University of Bari, Bari, Italy (C.F., S.S., M.A., R.T., M.I., R.R., P.G., M.P.); and Laval University, Department of Medicine, Quebec Heart Institute, Laval Hospital, Research Center, Sainte-Foy, Québec, Canada (M.C.).

Correspondence to Isabelle Deschênes, PhD, Heart and Vascular Research Center, MetroHealth Campus, Case Western Reserve University, 2500 MetroHealth Dr, Rammelkamp 658, Cleveland, OH 44109-1998. E-mail ideschenes{at}metrohealth.org

Received November 11, 2005; revision received May 10, 2006; accepted May 31, 2006.

Background— Brugada syndrome is associated with a high risk of sudden cardiac death and is caused by mutations in the cardiac voltage-gated sodium channel gene. Previously, the R282H-SCN5A mutation in the sodium channel gene was identified in patients with Brugada syndrome. In a family carrying the R282H-SCN5A mutation, an asymptomatic individual had a common H558R-SCN5A polymorphism and the mutation on separate chromosomes. Therefore, we hypothesized that the polymorphism could rescue the mutation.

Methods and Results— In heterologous cells, expression of the mutation alone did not produce sodium current. However, coexpressing the mutation with the polymorphism produced significantly greater current than coexpressing the mutant with the wild-type gene, demonstrating that the polymorphism rescues the mutation. Using immunocytochemistry, we demonstrated that the R282H-SCN5A construct can traffic to the cell membrane only in the presence of the H558R-SCN5A polymorphism. Using fluorescence resonance energy transfer and protein fragments centered on H558R-SCN5A, we demonstrated that cardiac sodium channels preferentially interact when the polymorphism is expressed on one protein but not the other.

Conclusions— This study suggests a mechanism whereby the Brugada syndrome has incomplete penetrance. More importantly, this study suggests that genetic polymorphisms may be a potential target for future therapies aimed at rescuing specific dysfunctional protein channels.

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