title: Paramyotonia congenita: from clinical diagnosis to in silico protein modeling analysis.
abstract: BACKGROUND
  Paramyotonia congenita (PMC) is an autosomal dominant disorder characterized by cold- or exercise-induced myotonia. PMC is caused by a mutation in SCN4A which encodes the α-subunit of the skeletal muscle sodium channel.
  
  
  METHODS
  The patient was an 11-year-old Japanese girl who was diagnosed as having PMC. To confirm the diagnosis, an orbital ice-pack test and blinking tests were performed. Next, to identify the mutation, genetic analysis of SCN4A was performed. Finally, to evaluate the mutation effect on the protein structure, in silico protein modeling analysis was performed.
  
  
  RESULTS
  Cold- and exercise-induced myotonia was reproduced in the patient with non-invasive bedside tests: ice-pack and blinking tests. In the genetic analysis, a missense mutation, c.4343G>A in SCN4A, was identified, which may result in an arginine to histidine substitution at 1448 in the protein sequence (p.Arg1448His). According to the protein modeling analysis, the mutation neutralized the positive electrostatic charge at 1448 in the DIV/S4 segment and disrupted the beginning of the helical structure in the DIV/S3-S4 linker of the SCN4A protein.
  
  
  CONCLUSIONS
  Diagnostic physical interventions in the patient confirmed the phenotype presentation consistent with PMC, and the in silico protein modeling analysis of p.Arg1448His predicted structural changes which can affect function of the protein. All the data confirmed the diagnosis of PMC in the patient and added to existing literature emphasizing the important role of arginine residue at 1448.
authors.affiliation: Department of Community Medicine and Social Health Care, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-Cho, Chuo-Ku, Kobe 650-0017, Japan.
authors.forename: Dian K
authors.initials: DK
authors.lastname: Nurputra
authors.forename: Taku
authors.initials: T
authors.lastname: Nakagawa
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Takeshima
authors.forename: Indra S K
authors.initials: IS
authors.lastname: Harahap
authors.forename: Satoru
authors.initials: S
authors.lastname: Morikawa
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Sakaeda
authors.forename: Poh San
authors.initials: PS
authors.lastname: Lai
authors.forename: Masafumi
authors.initials: M
authors.lastname: Matsuo
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Takaoka
authors.forename: Hisahide
authors.initials: H
authors.lastname: Nishio
mesh_terms: D000595:Amino Acid Sequence; D002648:Child; D003198:Computer Simulation; D005260:Female; D006801:Humans; D018482:Muscle, Skeletal / Q000378:metabolism*; D020125:Mutation, Missense; D020967:Myotonic Disorders / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism; D062553:NAV1.4 Voltage-Gated Sodium Channel / Q000737:chemistry / Q000235:genetics*; D015222:Sodium Channels / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
chemical_list: D062553:NAV1.4 Voltage-Gated Sodium Channel; C106251:SCN4A protein, human; D015222:Sodium Channels