title: Voltage sensor charge loss accounts for most cases of hypokalemic periodic paralysis.
abstract: BACKGROUND
  Several missense mutations of CACNA1S and SCN4A genes occur in hypokalemic periodic paralysis. These mutations affect arginine residues in the S4 voltage sensors of the channel. Approximately 20% of cases remain genetically undefined.
  
  
  METHODS
  We undertook direct automated DNA sequencing of the S4 regions of CACNA1S and SCN4A in 83 cases of hypokalemic periodic paralysis.
  
  
  RESULTS
  We identified reported CACNA1S mutations in 64 cases. In the remaining 19 cases, mutations in SCN4A or other CACNA1S S4 segments were found in 10, including three novel changes and the first mutations in channel domains I (SCN4A) and III (CACNA1S).
  
  
  CONCLUSIONS
  All mutations affected arginine residues, consistent with the gating pore cation leak hypothesis of hypokalemic periodic paralysis. Arginine mutations in S4 segments underlie 90% of hypokalemic periodic paralysis cases.
authors.affiliation: Medical Research Council Centre for Neuromuscular Diseases, Department of Molecular Neuroscience, Institute of Neurology and National Hospital for Neurology and Neurosurgery, Queen Square, London, WC1N 3BG, UK.
authors.forename: E
authors.initials: E
authors.lastname: Matthews
authors.forename: R
authors.initials: R
authors.lastname: Labrum
authors.forename: M G
authors.initials: MG
authors.lastname: Sweeney
authors.forename: R
authors.initials: R
authors.lastname: Sud
authors.forename: A
authors.initials: A
authors.lastname: Haworth
authors.forename: P F
authors.initials: PF
authors.lastname: Chinnery
authors.forename: G
authors.initials: G
authors.lastname: Meola
authors.forename: S
authors.initials: S
authors.lastname: Schorge
authors.forename: D M
authors.initials: DM
authors.lastname: Kullmann
authors.forename: M B
authors.initials: MB
authors.lastname: Davis
authors.forename: M G
authors.initials: MG
authors.lastname: Hanna
mesh_terms: D000293:Adolescent; D000595:Amino Acid Sequence / Q000235:genetics; D019943:Amino Acid Substitution / Q000235:genetics; D001120:Arginine / Q000235:genetics; D015220:Calcium Channels / Q000737:chemistry / Q000235:genetics*; D020746:Calcium Channels, L-Type; D004252:DNA Mutational Analysis; D005787:Gene Frequency / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing; D005838:Genotype; D006801:Humans; D040582:Inheritance Patterns / Q000235:genetics; D015640:Ion Channel Gating / Q000235:genetics; D008564:Membrane Potentials / Q000235:genetics; D009119:Muscle Contraction / Q000235:genetics; D018482:Muscle, Skeletal / Q000378:metabolism / Q000503:physiopathology; D009154:Mutation / Q000235:genetics*; D062553:NAV1.4 Voltage-Gated Sodium Channel; D020513:Paralysis, Hyperkalemic Periodic / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology*; D017434:Protein Structure, Tertiary / Q000235:genetics; D015222:Sodium Channels / Q000737:chemistry / Q000235:genetics*; D055815:Young Adult
chemical_list: C412223:CACNA1S protein, human; D015220:Calcium Channels; D020746:Calcium Channels, L-Type; D062553:NAV1.4 Voltage-Gated Sodium Channel; C106251:SCN4A protein, human; D015222:Sodium Channels; D001120:Arginine