title: R222Q SCN5A mutation is associated with reversible ventricular ectopy and dilated cardiomyopathy.
abstract: OBJECTIVE
  The goal of this study was to characterize a variant in the SCN5A gene that encodes the alpha-subunit of the cardiac sodium channel, Nav1.5, which was identified in 1 large kindred with dilated cardiomyopathy (DCM) and multiple arrhythmias, including premature ventricular complexes (PVCs).
  
  
  BACKGROUND
  Treatment guidelines for familial DCM are based on conventional heart failure therapies, and no gene-based interventions have been established.
  
  
  METHODS
  Family members underwent clinical evaluation and screening of the SCN5A and LMNA genes. Cellular electrophysiology and computational modeling were used to determine the functional consequences of the mutant Nav1.5 protein.
  
  
  RESULTS
  An R222Q missense variant located in a Nav1.5 voltage-sensing domain was identified in affected family members. Patch-clamp studies showed that R222Q Nav1.5 did not alter sodium channel current density, but did left shift steady-state parameters of activation and inactivation. Using a voltage ramp protocol, normalized current responses of R222Q channels were of earlier onset and greater magnitude than wild-type channels. Action potential modeling using Purkinje fiber and ventricular cell models suggested that rate-dependent ectopy of Purkinje fiber origin is the predominant ventricular effect of the R222Q variant and a potential cause of DCM. In R222Q carriers, there were only modest responses to heart failure therapies, but PVCs and DCM were substantially reduced by amiodarone or flecainide, which are drugs that have sodium channel-blocking properties.
  
  
  CONCLUSIONS
  The R222Q SCN5A variant has an activating effect on sodium channel function and is associated with reversible ventricular ectopy and DCM. Elucidation of the genetic basis of familial DCM can enable effective gene-targeted therapy to be implemented.
authors.affiliation: Molecular Cardiology and Biophysics Division, Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales, Australia.
authors.forename: Stefan A
authors.initials: SA
authors.lastname: Mann
authors.forename: Maria L
authors.initials: ML
authors.lastname: Castro
authors.forename: Monique
authors.initials: M
authors.lastname: Ohanian
authors.forename: Guanglan
authors.initials: G
authors.lastname: Guo
authors.forename: Poonam
authors.initials: P
authors.lastname: Zodgekar
authors.forename: Angela
authors.initials: A
authors.lastname: Sheu
authors.forename: Kathryn
authors.initials: K
authors.lastname: Stockhammer
authors.forename: Tina
authors.initials: T
authors.lastname: Thompson
authors.forename: David
authors.initials: D
authors.lastname: Playford
authors.forename: Rajesh
authors.initials: R
authors.lastname: Subbiah
authors.forename: Dennis
authors.initials: D
authors.lastname: Kuchar
authors.forename: Anu
authors.initials: A
authors.lastname: Aggarwal
authors.forename: Jamie I
authors.initials: JI
authors.lastname: Vandenberg
authors.forename: Diane
authors.initials: D
authors.lastname: Fatkin
mesh_terms: D000328:Adult; D000369:Aged, 80 and over; D000818:Animals; D016466:CHO Cells; D002311:Cardiomyopathy, Dilated / Q000188:drug therapy / Q000235:genetics* / Q000503:physiopathology; D006224:Cricetinae; D005260:Female; D006801:Humans; D034904:Lamin Type A / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000235:genetics*; D010641:Phenotype; D011690:Purkinje Fibers / Q000503:physiopathology; D018879:Ventricular Premature Complexes / Q000188:drug therapy / Q000235:genetics* / Q000503:physiopathology; D055815:Young Adult
chemical_list: C494847:LMNA protein, human; D034904:Lamin Type A; D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human