title: SCN10A/Nav1.8 modulation of peak and late sodium currents in patients with early onset atrial fibrillation.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors: Division of Cardiovascular Medicine, Vanderbilt University School of Medicine, 2215B Garland Avenue, Room 1285A MRB IV, Nashville, TN 37323-6602, USA.
authors: Eleonora
authors: E
authors: Savio-Galimberti
authors: Division of Clinical Pharmacology, Vanderbilt University School of Medicine, 2215B Garland Avenue, Room 1285A MRB IV, Nashville, TN 37323-6602, USA.
authors: Peter
authors: P
authors: Weeke
authors: Division of Cardiovascular Medicine, Vanderbilt University School of Medicine, 2215B Garland Avenue, Room 1285A MRB IV, Nashville, TN 37323-6602, USA.
authors: Raafia
authors: R
authors: Muhammad
authors: Division of Cardiovascular Medicine, Vanderbilt University School of Medicine, 2215B Garland Avenue, Room 1285A MRB IV, Nashville, TN 37323-6602, USA.
authors: Marcia
authors: M
authors: Blair
authors: Division of Cardiovascular Medicine, Vanderbilt University School of Medicine, 2215B Garland Avenue, Room 1285A MRB IV, Nashville, TN 37323-6602, USA.
authors: Sami
authors: S
authors: Ansari
authors: Division of Clinical Pharmacology, Vanderbilt University School of Medicine, 2215B Garland Avenue, Room 1285A MRB IV, Nashville, TN 37323-6602, USA.
authors: Laura
authors: L
authors: Short
authors: Division of Clinical Pharmacology, Vanderbilt University School of Medicine, 2215B Garland Avenue, Room 1285A MRB IV, Nashville, TN 37323-6602, USA.
authors: Thomas C
authors: TC
authors: Atack
authors: Division of Cardiovascular Medicine, Vanderbilt University School of Medicine, 2215B Garland Avenue, Room 1285A MRB IV, Nashville, TN 37323-6602, USA.
authors: Kaylen
authors: K
authors: Kor
authors: Division of Genetic Medicine, Vanderbilt University School of Medicine, Nashville, TN 37323-6602, USA.
authors: Carlos G
authors: CG
authors: Vanoye
authors: Danish National Research Centre for Cardiac Arrhythmia, Rigshospitalet, University of Copenhagen, Denmark.
authors: Morten Salling
authors: MS
authors: Olesen
authors: LuCamp, The Lundbeck Foundation Centre for Applied Medical Genomics in Personalized Disease Prediction, Copenhagen, Denmark.
authors: LuCamp
authors: Division of Clinical Pharmacology, Vanderbilt University School of Medicine, 2215B Garland Avenue, Room 1285A MRB IV, Nashville, TN 37323-6602, USA.
authors: Tao
authors: T
authors: Yang
authors: Division of Genetic Medicine, Vanderbilt University School of Medicine, Nashville, TN 37323-6602, USA.
authors: Alfred L
authors: AL
authors: George
authors: Division of Cardiovascular Medicine, Vanderbilt University School of Medicine, 2215B Garland Avenue, Room 1285A MRB IV, Nashville, TN 37323-6602, USA Division of Clinical Pharmacology, Vanderbilt University School of Medicine, 2215B Garland Avenue, Room 1285A MRB IV, Nashville, TN 37323-6602, USA.
authors: Dan M
authors: DM
authors: Roden
authors: Division of Cardiovascular Medicine, Vanderbilt University School of Medicine, 2215B Garland Avenue, Room 1285A MRB IV, Nashville, TN 37323-6602, USA Division of Clinical Pharmacology, Vanderbilt University School of Medicine, 2215B Garland Avenue, Room 1285A MRB IV, Nashville, TN 37323-6602, USA dawood.darbar@vanderbilt.edu.
authors: Dawood
authors: D
authors: Darbar
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D001281:Atrial Fibrillation / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D002460:Cell Line; D004252:DNA Mutational Analysis; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006339:Heart Rate; D006579:Heterozygote; D006801:Humans; D008297:Male; D008564:Membrane Potentials; D008875:Middle Aged; D009154:Mutation; D032383:Myocytes, Cardiac / Q000378:metabolism*; D062559:NAV1.8 Voltage-Gated Sodium Channel / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D012042:Registries; D012964:Sodium / Q000378:metabolism*; D013714:Tennessee; D013997:Time Factors; D014162:Transfection; D055815:Young Adult
chemical_list: D062559:NAV1.8 Voltage-Gated Sodium Channel; C568317:SCN10A protein, human; D012964:Sodium
keywords: Atrial fibrillation; Cardiac electrophysiology; Late sodium current; Nav1.8; SCN10A