SCN10A/Nav1.8 modulation of peak and late sodium currents in patients with early onset atrial fibrillation.

Savio-Galimberti E, Weeke P, Muhammad R, Blair M, Ansari S, Short L, Atack TC, Kor K, Vanoye CG, Olesen MS, LuCamp , Yang T, George AL, Roden DM, Darbar D
Cardiovasc Res. 2014 104 (2): 355-63

PMID: 25053638 · PMCID: PMC4271018 · DOI:10.1093/cvr/cvu170

AIMS - To test the hypothesis that vulnerability to atrial fibrillation (AF) is associated with rare coding sequence variation in the SCN10A gene, which encodes the voltage-gated sodium channel isoform NaV1.8 found primarily in peripheral nerves and to identify potentially disease-related mechanisms in high-priority rare variants using in-vitro electrophysiology.

METHODS AND RESULTS - We re-sequenced SCN10A in 274 patients with early onset AF from the Vanderbilt AF Registry to identify rare coding variants. Engineered variants were transiently expressed in ND7/23 cells and whole-cell voltage clamp experiments were conducted to elucidate their functional properties. Resequencing SCN10A identified 18 heterozygous rare coding variants (minor allele frequency ≤1%) in 18 (6.6%) AF probands. Four probands were carriers of two rare variants each and 14 were carriers of one coding variant. Based on evidence of co-segregation, initial assessment of functional importance, and presence in ≥1 AF proband, three variants (417delK, A1886V, and the compound variant Y158D-R814H) were selected for functional studies. The 417delK variant displayed near absent current while A1886V and Y158D-R814H exhibited enhanced peak and late (INa-L) sodium currents; both Y158D and R818H individually contributed to this phenotype.

CONCLUSION - Rare SCN10A variants encoding Nav1.8 were identified in 6.6% of patients with early onset AF. In-vitro electrophysiological studies demonstrated profoundly altered function in 3/3 high-priority variants. Collectively, these data strongly support the hypothesis that rare SCN10A variants may contribute to AF susceptibility.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: journals.permissions@oup.com.

MeSH Terms (26)

Adolescent Adult Aged Age of Onset Atrial Fibrillation Cell Line DNA Mutational Analysis Female Gene Frequency Genetic Predisposition to Disease Heart Rate Heterozygote Humans Male Membrane Potentials Middle Aged Mutation Myocytes, Cardiac NAV1.8 Voltage-Gated Sodium Channel Phenotype Registries Sodium Tennessee Time Factors Transfection Young Adult

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