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Original Articles

A Mutation in the β3 Subunit of the Cardiac Sodium Channel Associated With Brugada ECG Phenotype

Dan Hu, MD, PhD; Hector Barajas-Martinez, PhD; Elena Burashnikov, BS; Michael Springer, MD; Yuesheng Wu, MD; Andras Varro, MD, PhD; Ryan Pfeiffer, BS; Tamara T. Koopmann, PhD; Jonathan M. Cordeiro, PhD; Alejandra Guerchicoff, PhD; Guido D. Pollevick, PhD and Charles Antzelevitch, PhD

From the Masonic Medical Research Laboratory (D.H., H.-B.M., E.B., Y.W., R.P., J.M.C., A.G., G.D.P., C.A.), Utica, NY; Cardiology Department (M.S.), University of Louisville, Louisville, Ky; Heart Failure Research Center (T.T.K.), Academic Medical Center Amsterdam, The Netherlands; Department of Pharmacology and Pharmacotherapy (A.V.), University of Szeged, Szeged, Hungary; and Division for Cardiovascular Pharmacology (A.V.), Hungarian Academy of Sciences, Szeged, Hungary.

Correspondence to Charles Antzelevitch, PhD, Masonic Medical Research Laboratory, 2150 Bleecker St, Utica, NY. E-mail ca{at}mmrl.edu

Received October 15, 2008; accepted April 20, 2009.

Background— Brugada syndrome, characterized by ST-segment elevation in the right precordial ECG leads and the development of life-threatening ventricular arrhythmias, has been associated with mutations in 6 different genes. We identify and characterize a mutation in a new gene.

Methods and Results— A 64-year-old white male displayed a type 1 ST-segment elevation in V1 and V2 during procainamide challenge. Polymerase chain reaction-based direct sequencing was performed using a candidate gene approach. A missense mutation (L10P) was detected in exon 1 of SCN3B, the β3 subunit of the cardiac sodium channel, but not in any other gene known to be associated with Brugada syndrome or in 296 controls. Wild-type (WT) and mutant genes were expressed in TSA201 cells and studied using whole-cell patch-clamp techniques. Coexpression of SCN5A/WT+SCN1B/WT+SCN3B/L10P resulted in an 82.6% decrease in peak sodium current density, accelerated inactivation, slowed reactivation, and a –9.6-mV shift of half-inactivation voltage compared with SCN5A/WT+SCN1B/WT+SCN3B/WT. Confocal microscopy revealed that SCN5A/WT channels tagged with green fluorescent protein are localized to the cell surface when coexpressed with WT SCN1B and SCN3B but remain trapped in intracellular organelles when coexpressed with SCN1B/WT and SCN3B/L10P. Western blot analysis confirmed the presence of Na_Vβ3 in human ventricular myocardium.

Conclusions— Our results provide support for the hypothesis that mutations in SCN3B can lead to loss of transport and functional expression of the hNa_v1.5 protein, leading to reduction in sodium channel current and clinical manifestation of a Brugada phenotype.

Key Words: Brugada syndrome • arrhythmia • ion channels • SCN3B • protein trafficking

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CLINICAL PERSPECTIVE

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