title: Characterization of a new sodium channel mutation at arginine 1448 associated with moderate Paramyotonia congenita in humans.
abstract: 1. Paramyotonia congenita is a temperature-sensitive skeletal muscle disorder caused by missense mutations that occur in the adult skeletal muscle voltage-gated sodium channel. We report here the identification of a new genetic mutation in a family with the paramyotonia congenita phenotype. 2. Single-strand conformation polymorphism analysis and DNA sequencing showed that the defect was linked to a single nucleotide substitution causing an amino acid change from an arginine to a serine at position 1448 in the human sodium channel alpha-subunit. 3. Expression of the altered protein in human embryonic kidney (HEK) 293 cells revealed several defects in channel function: (i) the rate of fast inactivation was slower in the mutant channel compared with wild-type, (ii) steady-state fast inactivation was shifted towards hyperpolarizing potentials, (iii) the R1448S channels deactivated much more slowly, and (iv) the mutant channels recovered from the fast inactivated state more rapidly. 4. By contrast, the activation curve, steady-state slow inactivation and the rate of onset and recovery from slow inactivation were not altered by the R1448S mutation. 5. These data show that the defects observed in the sodium channel function could well explain the onset of the paramyotonia congenita in this family and emphasize the role of segment S4 of domain IV in sodium channel inactivation.
authors.affiliation: Howard Hughes Medical Institute, Eccles Institute of Human Genetics, University of Utah, Salt Lake City, UT 84112, USA. said@howard.genetics.utah.edu
authors.forename: S
authors.initials: S
authors.lastname: Bendahhou
authors.forename: T R
authors.initials: TR
authors.lastname: Cummins
authors.forename: H
authors.initials: H
authors.lastname: Kwiecinski
authors.forename: S G
authors.initials: SG
authors.lastname: Waxman
authors.forename: L J
authors.initials: LJ
authors.lastname: Ptácek
mesh_terms: D019943:Amino Acid Substitution; D001120:Arginine / Q000235:genetics* / Q000502:physiology; D002460:Cell Line; D004247:DNA / Q000032:analysis / Q000235:genetics; D004594:Electrophysiology; D006801:Humans; D007668:Kidney / Q000166:cytology; D007700:Kinetics; D008297:Male; D008564:Membrane Potentials / Q000502:physiology; D009224:Myotonia Congenita / Q000235:genetics*; D018408:Patch-Clamp Techniques; D010375:Pedigree; D010641:Phenotype; D016133:Polymerase Chain Reaction; D018807:Polymorphism, Single-Stranded Conformational; D015222:Sodium Channels / Q000235:genetics*
chemical_list: D015222:Sodium Channels; D004247:DNA; D001120:Arginine