Published Online
on April 21, 2009

A more recent version of this article appeared on June 1, 2009

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Original Article

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

Dan Hu¹; Hector Barajas–Martinez¹; Elena Burashnikov¹; Michael Springer²; Yuesheng Wu¹; Andras Varro³; Ryan Pfeiffer¹; Tamara T. Koopmann⁴; Jonathan M. Cordeiro¹; Alejandra Guerchicoff¹; Guido D. Pollevick¹ and Charles Antzelevitch^1,5

¹ Masonic Medical Research Laboratory, Utica, NY;
² University of Louisville, Louisville, KY;
³ University of Szeged, Szeged, Hungary;
⁴ Academic Medical Center Amsterdam, Amsterdam, The Netherlands

⁵ E-mail: ca{at}mmrl.edu

Background—Brugada Syndrome (BrS), 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 six different genes. Here, we identify and characterize a mutation in a new gene.

Methods and Results—A 64-year-old Caucasian male displayed a Type-1 ST segment elevation in V1 and V2 during procainamide challenge. Polymerase chain reaction (PCR)-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 BrS or in 296 controls. Wild type (WT) and mutant genes were expressed in TSA201 cells and studied using whole-cell patch-clamp techniques. Co-expression 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 to SCN5A/WT+SCN1B/WT+SCN3B/WT. Confocal microscopy revealed that SCN5A/WT channels tagged with green fluorescent protein (GFP) are localized to the cell surface when co-expressed with WT SCN1B and SCN3B, but remain trapped in intracellular organelles when co-expressed with SCN1B/WT and SCN3B/L10P. Western blot analysis confirmed the presence of NaVβ3 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: arrhythmia • ion channels • Brugada Syndrome • Protein Trafficking • SCN3B

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