A Mutation in the beta 3 Subunit of the Cardiac Sodium Channel Associated With Brugada ECG Phenotype

作者：Hu Dan; Barajas Martinez Hector; Burashnikov Elena; Springer Michael; Wu Yuesheng; Varro Andras; Pfeiffer Ryan; Koopmann Tamara T; Cordeiro Jonathan M; Guerchicoff Alejandra; Pollevick Guido D; Antzelevitch Charles^*

来源：Circulation-Cardiovascular Genetics, 2009, 2(3): 270-278.

DOI：10.1161/CIRCGENETICS.108.829192

• Brugada syndrome
• arrhythmia
• ion channels
• SCN3B
• protein trafficking

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 beta 3 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(V)beta 3 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(v)1.5 protein, leading to reduction in sodium channel current and clinical manifestation of a Brugada phenotype. (Circ Cardiovasc Genet. 2009; 2: 270-278.)

• 出版日期2009-6