title: Heterozygous mutations of the voltage-gated sodium channel SCN8A are associated with spike-wave discharges and absence epilepsy in mice.
abstract: In a chemical mutagenesis screen, we identified the novel Scn8a(8J) allele of the gene encoding the neuronal voltage-gated sodium channel Na(v)1.6. The missense mutation V929F in this allele alters an evolutionarily conserved residue in the pore loop of domain 2 of Na(v)1.6. Electroencephalography (EEG) revealed well-defined spike-wave discharges (SWD), the hallmark of absence epilepsy, in Scn8a(8J) heterozygotes and in heterozygotes for two classical Scn8a alleles, Scn8a(med) (null) and Scn8a(med-jo) (missense). Mouse strain background had a significant effect on SWD, with mutants on the C3HeB/FeJ strain showing a higher incidence than on C57BL/6J. The abnormal EEG patterns in heterozygous mutant mice and the influence of genetic background on SWD make SCN8A an attractive candidate gene for common human absence epilepsy, a genetically complex disorder.
authors.affiliation: Department of Human Genetics, Emory University, Atlanta, GA 30322, USA.
authors.forename: Ligia A
authors.initials: LA
authors.lastname: Papale
authors.forename: Barbara
authors.initials: B
authors.lastname: Beyer
authors.forename: Julie M
authors.initials: JM
authors.lastname: Jones
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Sharkey
authors.forename: Sergio
authors.initials: S
authors.lastname: Tufik
authors.forename: Michael
authors.initials: M
authors.lastname: Epstein
authors.forename: Verity A
authors.initials: VA
authors.lastname: Letts
authors.forename: Miriam H
authors.initials: MH
authors.lastname: Meisler
authors.forename: Wayne N
authors.initials: WN
authors.lastname: Frankel
authors.forename: Andrew
authors.initials: A
authors.lastname: Escayg
mesh_terms: D000818:Animals; D001483:Base Sequence; D004195:Disease Models, Animal; D004594:Electrophysiology; D004832:Epilepsy, Absence / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology*; D006579:Heterozygote; D006801:Humans; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009154:Mutation; D020125:Mutation, Missense; D062557:NAV1.6 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D015222:Sodium Channels / Q000235:genetics* / Q000378:metabolism
chemical_list: D062557:NAV1.6 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; C491046:Scn8a protein, mouse; D015222:Sodium Channels