title: Novel SCN5A mutation in amiodarone-responsive multifocal ventricular ectopy-associated cardiomyopathy.
abstract: BACKGROUND
  Mutations in SCN5A, which encodes the cardiac sodium channel NaV1.5, typically cause ventricular arrhythmia or conduction slowing. Recently, SCN5A mutations have been associated with heart failure combined with variable atrial and ventricular arrhythmia.
  
  
  OBJECTIVE
  The purpose of this study was to determine the clinical, genetic, and functional features of an amiodarone-responsive multifocal ventricular ectopy-related cardiomyopathy associated with a novel mutation in a NaV1.5 voltage sensor domain.
  
  
  METHODS
  A novel, de novo SCN5A mutation (NaV1.5-R225P) was identified in a boy with prenatal arrhythmia and impaired cardiac contractility followed by postnatal multifocal ventricular ectopy suppressible by amiodarone. We investigated the functional consequences of NaV1.5-R225P expressed heterologously in tsA201 cells.
  
  
  RESULTS
  Mutant channels exhibited significant abnormalities in both activation and inactivation leading to large, hyperpolarized window and ramp currents that predict aberrant sodium influx at potentials near the cardiomyocyte resting membrane potential. Mutant channels also exhibited significantly increased persistent (late) sodium current. This profile of channel dysfunction shares features with other SCN5A voltage sensor mutations associated with cardiomyopathy and overlapped that of congenital long QT syndrome. Amiodarone stabilized fast inactivation, suppressed persistent sodium current, and caused frequency-dependent inhibition of channel availability.
  
  
  CONCLUSIONS
  We determined the functional consequences and pharmacologic responses of a novel SCN5A mutation associated with an arrhythmia-associated cardiomyopathy. Comparisons with other cardiomyopathy-associated NaV1.5 voltage sensor mutations revealed a pattern of abnormal voltage dependence of activation as a shared biophysical mechanism of the syndrome.
authors.affiliation: Department of Pharmacology, Vanderbilt University, Nashville, Tennessee.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Beckermann
authors.affiliation: Royal Hospital for Sick Children, Yorkhill, Glasgow, Scotland, United Kingdom.
authors.forename: Karen
authors.initials: K
authors.lastname: McLeod
authors.affiliation: Royal Hospital for Sick Children, Yorkhill, Glasgow, Scotland, United Kingdom.
authors.forename: Victoria
authors.initials: V
authors.lastname: Murday
authors.affiliation: Division of Genetic Medicine, Department of Medicine, Vanderbilt University, Nashville, Tennessee.
authors.forename: Franck
authors.initials: F
authors.lastname: Potet
authors.affiliation: Department of Pharmacology, Vanderbilt University, Nashville, Tennessee; Division of Genetic Medicine, Department of Medicine, Vanderbilt University, Nashville, Tennessee. Electronic address: al.george@northwestern.edu.
authors.forename: Alfred L
authors.initials: AL
authors.lastname: George
mesh_terms: D000638:Amiodarone / Q000627:therapeutic use*; D000889:Anti-Arrhythmia Agents / Q000627:therapeutic use; D009202:Cardiomyopathies / Q000209:etiology* / Q000235:genetics / Q000503:physiopathology; D004247:DNA / Q000235:genetics*; D004252:DNA Mutational Analysis; D004562:Electrocardiography; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D009154:Mutation; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000235:genetics*; D018408:Patch-Clamp Techniques; D010375:Pedigree; D018879:Ventricular Premature Complexes / Q000150:complications / Q000188:drug therapy / Q000235:genetics*
chemical_list: D000889:Anti-Arrhythmia Agents; D062554:NAV1.5 Voltage-Gated Sodium Channel; D004247:DNA; D000638:Amiodarone
keywords: Amiodarone; Cardiomyopathy; Electrophysiology; SCN5A mutation