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

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Abstract
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 ofSCN3B, 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 ofSCN5A/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 withSCN5A/WT+SCN1B/WT+SCN3B/WT. Confocal microscopy revealed thatSCN5A/WT channels tagged with green fluorescent protein are localized to the cell surface when coexpressed with WTSCN1BandSCN3Bbut remain trapped in intracellular organelles when coexpressed withSCN1B/WT andSCN3B/L10P. Western blot analysis confirmed the presence of NaVβ3 in human ventricular myocardium.Conclusions—Our results provide support for the hypothesis that mutations inSCN3Bcan lead to loss of transport and functional expression of the hNav1.5 protein, leading to reduction in sodium channel current and clinical manifestation of a Brugada phenotype.