title: A novel dominant mutation of the Nav1.4 alpha-subunit domain I leading to sodium channel myotonia.
abstract: BACKGROUND
  Mutations in SCN4A may lead to myotonia.
  
  
  METHODS
  Presentation of a large family with myotonia, including molecular studies and patch clamp experiments using human embryonic kidney 293 cells expressing wild-type and mutated channels.
  
  
  RESULTS
  In a large family with historic data on seven generations and a clear phenotype, including myotonia at movement onset, with worsening by cold temperature, pregnancy, mental stress, and especially after rest after intense physical activity, but without weakness, the phenotype was linked with the muscle sodium channel gene (SCN4A) locus, in which a novel p.I141V mutation was found. This modification is located within the first transmembrane segment of domain I of the Na(v)1.4 alpha subunit, a region where no mutation has been reported so far. Patch clamp experiments revealed a mutation-induced hyperpolarizing shift (-12.9 mV) of the voltage dependence of activation, leading to a significant increase (approximately twofold) of the window current amplitude. In addition, the mutation shifted the voltage dependence of slow inactivation by -8.7 mV and accelerated the entry to this state.
  
  
  CONCLUSIONS
  We propose that the gain-of-function alteration in activation leads to the observed myotonic phenotype, whereas the enhanced slow inactivation may prevent depolarization-induced paralysis.
authors.affiliation: Department of Pharmacology and Toxicology, University of Lausanne, Switzerland.
authors.forename: S
authors.initials: S
authors.lastname: Petitprez
authors.forename: L
authors.initials: L
authors.lastname: Tiab
authors.forename: L
authors.initials: L
authors.lastname: Chen
authors.forename: L
authors.initials: L
authors.lastname: Kappeler
authors.forename: K M
authors.initials: KM
authors.lastname: Rösler
authors.forename: D
authors.initials: D
authors.lastname: Schorderet
authors.forename: H
authors.initials: H
authors.lastname: Abriel
authors.forename: J-M
authors.initials: JM
authors.lastname: Burgunder
mesh_terms: D002460:Cell Line; D004252:DNA Mutational Analysis / Q000379:methods; D005192:Family Health; D005260:Female; D006801:Humans; D007532:Isoleucine / Q000235:genetics; D008564:Membrane Potentials / Q000235:genetics / Q000502:physiology; D009154:Mutation; D009222:Myotonia / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D062553:NAV1.4 Voltage-Gated Sodium Channel; D021122:Protein Subunits / Q000235:genetics; D015222:Sodium Channels / Q000235:genetics*; D014162:Transfection / Q000379:methods; D014633:Valine / Q000235:genetics
chemical_list: D062553:NAV1.4 Voltage-Gated Sodium Channel; D021122:Protein Subunits; C106251:SCN4A protein, human; D015222:Sodium Channels; D007532:Isoleucine; D014633:Valine