title: Gain-of-function mutation in SCN5A causes ventricular arrhythmias and early onset atrial fibrillation.
abstract: BACKGROUND
  Mutations in SCN5A, the gene encoding the α-subunit of the cardiac sodium channel (NaV1.5), are associated with a broad spectrum of inherited cardiac arrhythmia disorders. The purpose of this study was to identify the genetic and functional determinants underlying a Dutch family that presented with a combined phenotype of ventricular arrhythmias with a likely adrenergic component, either in isolation or in combination with a mildly decreased heart function and early onset (<55years) atrial fibrillation.
  
  
  RESULTS
  We performed next generation sequencing in the proband of a two-generation Dutch family and demonstrated a novel missense mutation in SCN5A-(p.M1851V) which co-segregated with the clinical phenotype in the family. We functionally evaluated the putative genetic defect by patch clamp electrophysiological studies in human embryonic kidney cells transfected with mutant or wild-type Nav1.5. The current inactivation was slower and recovery from inactivation was faster in SCN5A-M1851V channels. The voltage dependence of inactivation was shifted towards more positive potentials and consequently, a larger TTX-sensitive window current was observed in SCN5A-M1851V channels. Furthermore, a higher upstroke velocity was observed for the SCN5A-M1851V channels, while the depolarization voltage was more negative, both indicating increased excitability.
  
  
  CONCLUSIONS
  This mutation leads to a gain-of-function mechanism based on increased channel availability and increased window current, fitting the observed clinical phenotype of (likely adrenergic-induced) ventricular arrhythmias and atrial fibrillation. These findings further expand the range of cardiac arrhythmias associated with mutations in SCN5A.
authors.affiliation: Heart Center, Department of Clinical and Experimental Cardiology, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Krystien V
authors.initials: KV
authors.lastname: Lieve
authors.affiliation: Heart Center, Department of Clinical and Experimental Cardiology, Academic Medical Center, Amsterdam, The Netherlands; Department of Anatomy, Embryology and Physiology, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Arie O
authors.initials: AO
authors.lastname: Verkerk
authors.affiliation: Heart Center, Department of Clinical and Experimental Cardiology, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Svitlana
authors.initials: S
authors.lastname: Podliesna
authors.affiliation: Heart Center, Department of Clinical and Experimental Cardiology, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Christian
authors.initials: C
authors.lastname: van der Werf
authors.affiliation: Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Tanck
authors.affiliation: Heart Center, Department of Clinical and Experimental Cardiology, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Nynke
authors.initials: N
authors.lastname: Hofman
authors.affiliation: Department of Cardiology, Westfriesgasthuis, Hoorn, The Netherlands.
authors.forename: Paul F
authors.initials: PF
authors.lastname: van Bergen
authors.affiliation: Heart Center, Department of Clinical and Experimental Cardiology, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Leander
authors.initials: L
authors.lastname: Beekman
authors.affiliation: Heart Center, Department of Clinical and Experimental Cardiology, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Connie R
authors.initials: CR
authors.lastname: Bezzina
authors.affiliation: Heart Center, Department of Clinical and Experimental Cardiology, Academic Medical Center, Amsterdam, The Netherlands; Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders, Jeddah, Saudi Arabia.
authors.forename: Arthur A M
authors.initials: AAM
authors.lastname: Wilde
authors.affiliation: Heart Center, Department of Clinical and Experimental Cardiology, Academic Medical Center, Amsterdam, The Netherlands. Electronic address: E.M.Lodder@amc.uva.nl.
authors.forename: Elisabeth M
authors.initials: EM
authors.lastname: Lodder
mesh_terms: D000293:Adolescent; D000328:Adult; D001281:Atrial Fibrillation / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense / Q000235:genetics*; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000235:genetics*; D010375:Pedigree; D014693:Ventricular Fibrillation / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology; D055815:Young Adult
chemical_list: D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human
keywords: Arrhythmia; Atrial fibrillation; Genetics; Inherited channelopathies; SCN5A mutation; Ventricular ectopy