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

Eleonora Savio-Galimberti, Peter Weeke, Raafia Muhammad, Marcia Blair, Sami Ansari, Laura Short, Thomas C. Atack, Kaylen Kor, Carlos G. Vanoye, Morten Salling Olesen, Lu Camp, Tao Yang, Alfred L. George, Dan M. Roden, Dawood Darbar*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

48 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)355-363
Number of pages9
JournalCardiovascular research
Volume104
Issue number2
DOIs
StatePublished - Nov 1 2014

Keywords

  • Atrial fibrillation
  • Cardiac electrophysiology
  • Late sodium current
  • Nav1.8
  • SCN10A

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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