title: A novel NaV1.5 voltage sensor mutation associated with severe atrial and ventricular arrhythmias.
abstract: BACKGROUND
  Inherited autosomal dominant mutations in cardiac sodium channels (NaV1.5) cause various arrhythmias, such as long QT syndrome and Brugada syndrome. Although dozens of mutations throughout the protein have been reported, there are few reported mutations within a voltage sensor S4 transmembrane segment and few that are homozygous. Here we report analysis of a novel lidocaine-sensitive recessive mutation, p.R1309H, in the NaV1.5 DIII/S4 voltage sensor in a patient with a complex arrhythmia syndrome.
  
  
  RESULTS
  We expressed the wild type or mutant NaV1.5 heterologously for analysis with the patch-clamp and voltage clamp fluorometry (VCF) techniques. p.R1309H depolarized the voltage-dependence of activation, hyperpolarized the voltage-dependence of inactivation, and slowed recovery from inactivation, thereby reducing the channel availability at physiologic membrane potentials. Additionally, p.R1309H increased the "late" Na(+) current. The location of the mutation in DIIIS4 prompted testing for a gating pore current. We observed an inward current at hyperpolarizing voltages that likely exacerbates the loss-of-function defects at resting membrane potentials. Lidocaine reduced the gating pore current.
  
  
  CONCLUSIONS
  The p.R1309H homozygous NaV1.5 mutation conferred both gain-of-function and loss-of-function effects on NaV1.5 channel activity. Reduction of a mutation-induced gating pore current by lidocaine suggested a therapeutic mechanism.
authors.affiliation: Division of Cardiology, Department of Medicine, Duke University Medical Center, Durham, NC, United States; Ion Channel Research Unit, Duke University Medical Center, Durham, NC, United States.
authors.forename: Hong-Gang
authors.initials: HG
authors.lastname: Wang
authors.affiliation: Department of Biomedical Engineering, Washington University in St. Louis, United States.
authors.forename: Wandi
authors.initials: W
authors.lastname: Zhu
authors.affiliation: Division of Cardiology, Nicklaus Children's Hospital, Miami, FL, United States.
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Kanter
authors.affiliation: Department of Biomedical Engineering, Washington University in St. Louis, United States.
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Silva
authors.affiliation: Department of Pediatrics, Children's Hospital of Eastern Ontario, Ottawa, Canada.
authors.forename: Christina
authors.initials: C
authors.lastname: Honeywell
authors.affiliation: Department of Pediatrics, Children's Hospital of Eastern Ontario, Ottawa, Canada.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Gow
authors.affiliation: Division of Cardiology, Department of Medicine, Duke University Medical Center, Durham, NC, United States; Ion Channel Research Unit, Duke University Medical Center, Durham, NC, United States; Department of Neurobiology, Duke University Medical Center, Durham, NC, United States. Electronic address: geoffrey.pitt@duke.edu.
authors.forename: Geoffrey S
authors.initials: GS
authors.lastname: Pitt
mesh_terms: D001145:Arrhythmias, Cardiac / Q000188:drug therapy / Q000235:genetics* / Q000503:physiopathology; D053840:Brugada Syndrome / Q000188:drug therapy / Q000235:genetics* / Q000503:physiopathology; D000075224:Cardiac Conduction System Disease; D006329:Heart Conduction System / Q000503:physiopathology*; D006801:Humans; D007223:Infant; D008012:Lidocaine / Q000008:administration & dosage; D008297:Male; D008564:Membrane Potentials / Q000235:genetics; D009154:Mutation; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D018408:Patch-Clamp Techniques
chemical_list: D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; D008012:Lidocaine
keywords: Atrial arrhythmia; Gating pore current; Na(V)1.5; R1309H mutation; S4 segment; Ventricular arrhythmia; Voltage sensor