title: Gating defects of a novel Na+ channel mutant causing hypokalemic periodic paralysis.
abstract: Hypokalemic periodic paralysis type 2 (hypoPP2) is an inherited skeletal muscle disorder caused by missense mutations in the SCN4A gene encoding the alpha subunit of the skeletal muscle Na+ channel (Nav1.4). All hypoPP2 mutations reported so far target an arginine residue of the voltage sensor S4 of domain II (R672/G/H/S). We identified a novel hypoPP2 mutation that neutralizes an arginine residue in DIII-S4 (R1132Q), and studied its functional consequences in HEK cells transfected with the human SCN4A cDNA. Whole-cell current recordings revealed an enhancement of both fast and slow inactivation, as well as a depolarizing shift of the activation curve. The unitary Na+ conductance remained normal in R1132Q and in R672S mutants, and cannot therefore account for the reduction of Na+ current presumed in hypoPP2. Altogether, our results provide a clear evidence for the role of R1132 in channel activation and inactivation, and confirm loss of function effects of hypoPP2 mutations leading to muscle hypoexcitability.
authors.affiliation: INSERM U546, Faculté de Médecine P & M Curie, 75013 Paris, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Carle
authors.forename: Loïc
authors.initials: L
authors.lastname: Lhuillier
authors.forename: Sandrine
authors.initials: S
authors.lastname: Luce
authors.forename: Damien
authors.initials: D
authors.lastname: Sternberg
authors.forename: Olivier
authors.initials: O
authors.lastname: Devuyst
authors.forename: Bertrand
authors.initials: B
authors.lastname: Fontaine
authors.forename: Nacira
authors.initials: N
authors.lastname: Tabti
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D001120:Arginine / Q000235:genetics; D005973:Glutamine / Q000235:genetics; D006801:Humans; D020514:Hypokalemic Periodic Paralysis / Q000235:genetics* / Q000503:physiopathology; D015640:Ion Channel Gating / Q000235:genetics*; D008297:Male; D062553:NAV1.4 Voltage-Gated Sodium Channel; D010375:Pedigree; D017354:Point Mutation; D015222:Sodium Channels / Q000235:genetics* / Q000502:physiology*
chemical_list: D062553:NAV1.4 Voltage-Gated Sodium Channel; C106251:SCN4A protein, human; D015222:Sodium Channels; D005973:Glutamine; D001120:Arginine