title: Functional characterization of the D188V mutation in neuronal voltage-gated sodium channel causing generalized epilepsy with febrile seizures plus (GEFS).
abstract: Mutations in the alpha 1 subunit of the voltage-gated sodium channel (SCN1A) have been increasingly recognized as an important cause of familial epilepsy in humans. However, the functional consequences of these mutations remain largely unknown. We identified a mutation (D188V) in SCN1A segregating with generalized epilepsy with febrile seizures (GEFS) in a large kindred. Compared to wild-type sodium channels, in vitro expression of channels harboring the D188V mutation were found to be more resistant to the decline in amplitude that is normally observed over the course of high frequency pulse trains. This small change on a single aspect of channel function is compatible with an increase in membrane excitability, such as during sustained and uncontrolled neuronal discharges. These data suggest that this specific effect on sodium channel function could be a general mechanism in the pathophysiology of epilepsies caused by mutations in sodium channels in humans.
authors.affiliation: Center for Research in Neuroscience, McGill University Health Center Research Institute, McGill University, The Montreal General Hospital, 1650 Cedar Avenue, Quebec, H3G 1A4, Montreal, Canada.
authors.forename: Patrick
authors.initials: P
authors.lastname: Cossette
authors.forename: Andrew
authors.initials: A
authors.lastname: Loukas
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Lafrenière
authors.forename: Daniel
authors.initials: D
authors.lastname: Rochefort
authors.forename: Eric
authors.initials: E
authors.lastname: Harvey-Girard
authors.forename: David S
authors.initials: DS
authors.lastname: Ragsdale
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Dunn
authors.forename: Guy A
authors.initials: GA
authors.lastname: Rouleau
mesh_terms: D000818:Animals; D002462:Cell Membrane / Q000502:physiology; D004594:Electrophysiology; D004829:Epilepsy, Generalized / Q000235:genetics* / Q000503:physiopathology; D005334:Fever / Q000503:physiopathology*; D006801:Humans; D008564:Membrane Potentials / Q000502:physiology; D016296:Mutagenesis; D062550:NAV1.1 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009474:Neurons / Q000502:physiology*; D010641:Phenotype; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012640:Seizures / Q000235:genetics* / Q000503:physiopathology; D015222:Sodium Channels / Q000235:genetics* / Q000502:physiology
chemical_list: D062550:NAV1.1 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; C568242:SCN1A protein, human; C568250:Scn1a protein, rat; D015222:Sodium Channels