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Rigshospitalet - a part of Copenhagen University Hospital
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SCN10A/Nav1.8 modulation of peak and late sodium currents in patients with early onset atrial fibrillation

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  • Eleonora Savio-Galimberti
  • Peter Weeke
  • Raafia Muhammad
  • Marcia Blair
  • Sami Ansari
  • Laura Short
  • Thomas C Atack
  • Kaylen Kor
  • Carlos G Vanoye
  • Morten Salling Olesen
  • LuCamp
  • Tao Yang
  • Alfred L George
  • Dan M Roden
  • Dawood Darbar
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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
JournalCardiovascular Research
Volume104
Issue number2
Pages (from-to)355-63
Number of pages9
ISSN0008-6363
DOIs
Publication statusPublished - 1 Nov 2014

ID: 45069894