Published Online
on July 24, 2006

A more recent version of this article appeared on August 1, 2006

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Submitted on November 11, 2005
Revised on May 10, 2006
Accepted on May 31, 2006

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, and 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.).

^* To whom correspondence should be addressed. E-mail: ideschenes{at}metrohealth.org.

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.

Key words: amino acids • electrophysiology • genes • ion channels • sodium

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