Heterozygous mutations of the voltage-gated sodium channel SCN8A are associated with spike-wave discharges and absence epilepsy in mice.
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.
Papale
Ligia A
LA
Department of Human Genetics, Emory University, Atlanta, GA 30322, USA.
Beyer
Barbara
B
Jones
Julie M
JM
Sharkey
Lisa M
LM
Tufik
Sergio
S
Epstein
Michael
M
Letts
Verity A
VA
Meisler
Miriam H
MH
Frankel
Wayne N
WN
Escayg
Andrew
A
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
D062557:NAV1.6 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; C491046:Scn8a protein, mouse; D015222:Sodium Channels