title: Functional effects of two voltage-gated sodium channel mutations that cause generalized epilepsy with febrile seizures plus type 2.
abstract: Two mutations that cause generalized epilepsy with febrile seizures plus (GEFS+) have been identified previously in the SCN1A gene encoding the alpha subunit of the Na(v)1.1 voltage-gated sodium channel (Escayg et al., 2000). Both mutations change conserved residues in putative voltage-sensing S4 segments, T875M in domain II and R1648H in domain IV. Each mutation was cloned into the orthologous rat channel rNa(v)1.1, and the properties of the mutant channels were determined in the absence and presence of the beta1 subunit in Xenopus oocytes. Neither mutation significantly altered the voltage dependence of either activation or inactivation in the presence of the beta1 subunit. The most prominent effect of the T875M mutation was to enhance slow inactivation in the presence of beta1, with small effects on the kinetics of recovery from inactivation and use-dependent activity of the channel in both the presence and absence of the beta1 subunit. The most prominent effects of the R1648H mutation were to accelerate recovery from inactivation and decrease the use dependence of channel activity with and without the beta1 subunit. The DIV mutation would cause a phenotype of sodium channel hyperexcitability, whereas the DII mutation would cause a phenotype of sodium channel hypoexcitability, suggesting that either an increase or decrease in sodium channel activity can result in seizures.
authors.affiliation: Department of Microbiology and Molecular Genetics, University of California, Irvine, California 92697-4025, USA.
authors.forename: J
authors.initials: J
authors.lastname: Spampanato
authors.forename: A
authors.initials: A
authors.lastname: Escayg
authors.forename: M H
authors.initials: MH
authors.lastname: Meisler
authors.forename: A L
authors.initials: AL
authors.lastname: Goldin
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D002478:Cells, Cultured; D004829:Epilepsy, Generalized / Q000150:complications / Q000235:genetics*; D015870:Gene Expression; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008954:Models, Biological; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D062550:NAV1.1 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism*; D009865:Oocytes / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010641:Phenotype; D021122:Protein Subunits; D051381:Rats; D003294:Seizures, Febrile / Q000150:complications / Q000235:genetics*; D012964:Sodium / Q000378:metabolism; D015222:Sodium Channels / Q000235:genetics* / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013577:Syndrome; D013779:Tetrodotoxin / Q000494:pharmacology; D014162:Transfection
chemical_list: D062550:NAV1.1 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; D021122:Protein Subunits; C568250:Scn1a protein, rat; D015222:Sodium Channels; D013779:Tetrodotoxin; D012964:Sodium