title: Phenotypic characterization of a novel long-QT syndrome mutation (R1623Q) in the cardiac sodium channel.
abstract: BACKGROUND
  A heritable form of the long-QT syndrome (LQT3) has been linked to mutations in the cardiac sodium channel gene (SCN5A). Recently, a sporadic SCN5A mutation was identified in a Japanese girl afflicted with the long-QT syndrome. In contrast to the heritable mutations, this externally positioned domain IV, S4 mutation (R1623Q) neutralized a charged residue that is critically involved in activation-inactivation coupling.
  
  
  RESULTS
  We have characterized the R1623Q mutation in the human cardiac sodium channel (hH1) using both whole-cell and single-channel recordings. In contrast to the autosomal dominant LQT3 mutations, R1623Q increased the probability of long openings and caused early reopenings, producing a threefold prolongation of sodium current decay. Lidocaine restored rapid decay of the R1623Q macroscopic current.
  
  
  CONCLUSIONS
  The R1623Q mutation produces inactivation gating defects that differ mechanistically from those caused by LQT3 mutations. These findings provide a biophysical explanation for this severe long-QT phenotype and extend our understanding of the mechanistic role of the S4 segment in cardiac sodium channel inactivation gating and class I antiarrhythmic drug action.
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, Md 21287, USA.
authors.forename: N G
authors.initials: NG
authors.lastname: Kambouris
authors.forename: H B
authors.initials: HB
authors.lastname: Nuss
authors.forename: D C
authors.initials: DC
authors.lastname: Johns
authors.forename: G F
authors.initials: GF
authors.lastname: Tomaselli
authors.forename: E
authors.initials: E
authors.lastname: Marban
authors.forename: J R
authors.initials: JR
authors.lastname: Balser
mesh_terms: D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D005260:Female; D005799:Genes, Dominant; D006801:Humans; D008012:Lidocaine / Q000494:pharmacology; D008133:Long QT Syndrome / Q000235:genetics* / Q000378:metabolism; D016297:Mutagenesis, Site-Directed; D062554:NAV1.5 Voltage-Gated Sodium Channel; D009865:Oocytes / Q000187:drug effects; D018408:Patch-Clamp Techniques; D010641:Phenotype; D017354:Point Mutation; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015222:Sodium Channels / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D014981:Xenopus
chemical_list: D000889:Anti-Arrhythmia Agents; D062554:NAV1.5 Voltage-Gated Sodium Channel; D011993:Recombinant Fusion Proteins; C568320:SCN5A protein, human; D015222:Sodium Channels; D008012:Lidocaine