title: An epilepsy mutation in the sodium channel SCN1A that decreases channel excitability.
abstract: Mutations in three voltage-gated sodium channel genes, SCN1A, SCN2A, and SCN1B, and two GABAA receptor subunit genes, GABRG2 and GABRD, have been identified in families with generalized epilepsy with febrile seizures plus (GEFS+). A novel mutation, R859C, in the Nav1.1 sodium channel was identified in a four-generation, 33-member Caucasian family with a clinical presentation consistent with GEFS+. The mutation neutralizes a positively charged arginine in the domain 2 S4 voltage sensor of the Nav1.1 channel alpha subunit. This residue is conserved in mammalian sodium channels as well as in sodium channels from lower organisms. When the mutation was placed in the rat Nav1.1 channel and expressed in Xenopus oocytes, the mutant channel displayed a positive shift in the voltage dependence of sodium channel activation, slower recovery from slow inactivation, and lower levels of current compared with the wild-type channel. Computational analysis suggests that neurons expressing the mutant channel have higher thresholds for firing a single action potential and for firing multiple action potentials, along with decreased repetitive firing. Therefore, this mutation should lead to decreased neuronal excitability, in contrast to most previous GEFS+ sodium channel mutations, which have changes predicted to increase neuronal firing.
authors.affiliation: Department of Microbiology and Molecular Genetics, University of California, Irvine, California 92697-4025, USA.
authors.forename: Arthur J
authors.initials: AJ
authors.lastname: Barela
authors.forename: Salina P
authors.initials: SP
authors.lastname: Waddy
authors.forename: Jay G
authors.initials: JG
authors.lastname: Lickfett
authors.forename: Jessica
authors.initials: J
authors.lastname: Hunter
authors.forename: Aimee
authors.initials: A
authors.lastname: Anido
authors.forename: Sandra L
authors.initials: SL
authors.lastname: Helmers
authors.forename: Alan L
authors.initials: AL
authors.lastname: Goldin
authors.forename: Andrew
authors.initials: A
authors.lastname: Escayg
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D000818:Animals; D001120:Arginine / Q000235:genetics; D002460:Cell Line; D002648:Child; D003545:Cysteine / Q000235:genetics; D004307:Dose-Response Relationship, Radiation; D004827:Epilepsy / Q000235:genetics* / Q000503:physiopathology; D005192:Family Health; D005260:Female; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D008958:Models, Molecular; D008959:Models, Neurological; D016296:Mutagenesis / Q000502:physiology; D009154:Mutation; D062550:NAV1.1 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009865:Oocytes; D018408:Patch-Clamp Techniques / Q000379:methods; D051381:Rats; D026941:Sodium Channel Blockers / Q000494:pharmacology; D015222:Sodium Channels / Q000235:genetics*; D013779:Tetrodotoxin / Q000494:pharmacology; D014981:Xenopus
chemical_list: D062550:NAV1.1 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; C568242:SCN1A protein, human; C568250:Scn1a protein, rat; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D013779:Tetrodotoxin; D001120:Arginine; D003545:Cysteine