Abstract 17782: Both Common and Rare SCN10A Variants Associated with Brugada Syndrome Displayed an Increase in Late Nav1.8 Sodium Currents in ND 7/23 cells
Introduction: Brugada syndrome (BrS) is an oligogenic disease, often linked to mutations in SCN5A encoding the canonical cardiac sodium channel. Prolongation of QRS interval implicates slowed cardiac conduction as an important element of the BrS arrhythmia phenotype. Recent genome-wide association studies have implicated common variation in SCN10A as a potential modulator of cardiac conduction. SCN10A encodes the tetrodotoxin-resistant voltage-gated sodium channel isoform Nav1.8 primarily found in dorsal root ganglia and at lower levels in the heart. A recent candidate gene sequencing study identified 5 non-synonymous SCN10A rare variants in 4/156 white SCN5A mutation-negative patients with BrS and one protective non-synonymous common variant V1073A [(T>C): T allele BrS vs. control: 65.1% vs. 40.1%, P = 3.54x10-19].
Hypothesis: Here we tested the hypothesis that the common variant (V1073A) and 2 of the rare variants identified (A200V, I671V) generate aberrant Nav1.8 function and this may contribute to BrS phenotype.
Methods: We studied the SCN10A common variant V1073A and the SCN10A rare variants A200V and I671V in transiently transfected ND7/23 cells. After 48-hr incubation at 37°C, macroscopic sodium currents were measured at room temperature using whole-cell voltage-clamp technique.
Results: V1073A common variant demonstrated two-fold increase in both peak (INa-Peak) and late (INa-L, measured 100-ms post-depolarization) sodium currents compared to WT. By contrast, both rare variants demonstrated significant reductions in INa-Peak (A200V: -16.5±3 pA/pF [mutant] vs. -37.8±4.9 pA/pF [WT], P<0.01; I671V: -25.5±1.6 pA/pF [mutant] vs. -37.8±4.9 pA/pF [WT], P<0.05, all n=7 cells/group) but increased INa-L (A200V: 24.2±3.3% of INa-Peak; I671V: 15.8±1.6% of INa-Peak) compared to WT (7.8±1.3% of INa-Peak). Incubation of cells transfected with either A200V or I671V rare variants at 28oC instead of 37oC did not rescue the reduction observed in peak currents.
Conclusions: SCN10A variants associated with BrS displayed a range of strikingly altered functions in a heterologous expression system (ND7/23 cells), which support our hypothesis that they contribute to BrS phenotype.
Author Disclosures: E. Savio-Galimberti: None. T. Yang: None. D.M. Roden: None. E.R. Behr: None. K.C. Kor: None. Y. Jamshidi: None. E. Petropoulou: None. P. Guicheney: None. J. Tfelt-Hansen: None. A.A. Wilde: None. C.R. Bezzina: None. M.S. Olesen: None. A.G. Holst: None. M.J. Ackerman: None. P.J. Schwartz: None. L. Crotti: None. V. Probst: None. R. Redon: None. D. Darbar: None.
This research has received full or partial funding support from the American Heart Association.
- © 2014 by American Heart Association, Inc.