title: A novel sodium channel mutation in a family with hypokalemic periodic paralysis.
abstract: OBJECTIVE
  To identify the cause of hypokalemic periodic paralysis (HOKPP) in a family whose disease is not caused by a mutation in the dihydropyridine-sensitive (DHP) receptor alpha1-subunit gene (CACNA1S).
  
  
  BACKGROUND
  Hypokalemic periodic paralysis is primarily caused by mutations within CACNA1S. Genetic heterogeneity for HOKPP has been reported, but no other locus has been identified.
  
  
  METHODS
  Single-stranded conformational polymorphism (SSCP) analysis and PCR direct sequencing were used to screen the skeletal muscle alpha1-sodium channel gene (SCN4A) for a mutation in our family.
  
  
  RESULTS
  SSCP analysis showed an abnormally migrating conformer in exon 12. Direct sequencing of the conformer showed a guanine to adenine transition at position 2006 in the cDNA sequence; this results in an amino acid substitution of a highly conserved arginine (Arg) to histidine (His) at position 669. This sequence alteration segregated only with the affected members of the kindred and was not found in a panel of 100 DNA samples from healthy controls. The amino acid substitution alters the outermost positive charge in the membrane spanning segment DII/S4, which is involved in voltage sensing.
  
  
  CONCLUSIONS
  The first arginine in DII/S4 and in DIV/S4 within the skeletal muscle sodium channel and the L-type calcium channel genie CACNA1S appear to be critical for normal function. In all four cases, Arg to His mutations result in a disease phenotype. The identification of a mutation within the skeletal muscle sodium channel resulting in hypokalemic periodic paralysis represents a novel finding.
authors.affiliation: Division of Neurology, Ottawa General Hospital, Ottawa Hospital Research Institute, Ontario, Canada. dbulman@ogh.on.ca
authors.forename: D E
authors.initials: DE
authors.lastname: Bulman
authors.forename: K A
authors.initials: KA
authors.lastname: Scoggan
authors.forename: M D
authors.initials: MD
authors.lastname: van Oene
authors.forename: M W
authors.initials: MW
authors.lastname: Nicolle
authors.forename: A F
authors.initials: AF
authors.lastname: Hahn
authors.forename: L L
authors.initials: LL
authors.lastname: Tollar
authors.forename: G C
authors.initials: GC
authors.lastname: Ebers
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence / Q000235:genetics; D019943:Amino Acid Substitution / Q000235:genetics*; D001120:Arginine / Q000235:genetics; D004576:Electromyography; D006639:Histidine / Q000235:genetics; D006801:Humans; D020514:Hypokalemic Periodic Paralysis / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D008969:Molecular Sequence Data; D062553:NAV1.4 Voltage-Gated Sodium Channel; D010375:Pedigree; D010641:Phenotype; D018807:Polymorphism, Single-Stranded Conformational; D015222:Sodium Channels / Q000235:genetics*
chemical_list: D062553:NAV1.4 Voltage-Gated Sodium Channel; C106251:SCN4A protein, human; D015222:Sodium Channels; D006639:Histidine; D001120:Arginine