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(Circulation Research. 2001;88:e78.)
© 2001 American Heart Association, Inc.

UltraRapid Communication

Novel Mechanism for Brugada Syndrome

Defective Surface Localization of an SCN5A Mutant (R1432G)

Ghayath Baroudi, Valerie Pouliot, Isabelle Denjoy, Pascale Guicheney, Alvin Shrier, Mohamed Chahine

From Laval University, Department of Medicine (G.B., V.P., M.C.) and Québec Heart Institute, Laval Hospital, Research Center (G.B., V.P., M.C.), Sainte-Foy, Québec, Canada; Service de Cardiologie, Hôpital Lariboisière (I.D.) and INSERM U523, Institut de Myologie, IFR "Cur, muscles et vaisseaux" No. 14, Groupe hospitalier Pitié-Salpêtrière (P.G.), Paris, France; and Department of Physiology, McGill University (A.S.), Montreal, Canada.

Correspondence to Dr M. Chahine, Laval Hospital Research Center, 2725 Chemin Sainte-Foy, Sainte-Foy, Québec, Canada G1V 4G5. E-mail Mohamed.Chahine{at}phc.ulaval.ca

Abstract

Abstract—The SCN5A gene encodes the subunit of the human heart sodium channel (hH1), which plays a critical role in cardiac excitability. Mutations of SCN5A underlie Brugada syndrome, an inherited disorder that leads to ventricular fibrillation and sudden death. This study describes changes in cellular localization and functional expression of hH1 in a naturally occurring SCN5A mutation (R1432G) reported for Brugada syndrome. Using patch-clamp experiments, we show that there is an abolition of functional hH1 expression in R1432G mutants expressed in human tsA201 cells but not in Xenopus oocytes. In tsA201 cells, a conservative positively charged mutant, R1432K, produced sodium currents with normal gating properties, whereas other mutations at this site abolished functional sodium channel expression. Immunofluorescent staining and confocal microscopy showed that the wild-type subunit expressed in tsA201 cells was localized to the cell surface, whereas the R1432G mutant was colocalized with calnexin within the endoplasmic reticulum. The ß₁ subunit was also localized to the cell surface in the presence of the subunit; however, in its absence, the ß₁ subunit was restricted to a perinuclear localization. These results demonstrate that the disruption of SCN5A cell-surface localization is one mechanism that can account for the loss of functional sodium channels in Brugada syndrome. The full text of this article is available at http://www.circresaha.org.

Key Words: sodium channels • cardiac arrhythmias • protein trafficking • Brugada syndrome • ion channels

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