The voltage-gated sodium channel Scn8a is a genetic modifier of severe myoclonic epilepsy of infancy.
The mammalian genome contains four voltage-gated sodium channel genes that are primarily expressed in the central nervous system: SCN1A, SCN2A, SCN3A and SCN8A. Mutations in SCN1A and SCN2A are responsible for several dominant idiopathic epilepsy disorders, including generalized epilepsy with febrile seizures plus (GEFS+) and severe myoclonic epilepsy of infancy (SMEI). Mutations in SCN8A are associated with cognitive deficits and neuropsychiatric illness in humans and movement disorders in mice; however, a role for SCN8A (Na(v)1.6) in epilepsy has not been investigated. To determine the relationship between Na(v)1.6 dysfunction and seizure susceptibility, we examined the thresholds of two Scn8a mouse mutants, Scn8a(med) and Scn8a(med-jo), to flurothyl- and kainic acid (KA)-induced seizures. Both mutants were more seizure resistant than wild-type littermates, suggesting that altered Na(v)1.6 function reduces neuronal excitability. To determine whether impaired Na(v)1.6 function could ameliorate seizure severity in a mouse model of SMEI, we generated Scn1a(+/-); Scn8a(med-jo/+) double heterozygous mice. Unlike Scn1a(+/-) mice that are more susceptible to flurothyl-induced seizures, Scn1a(+/-); Scn8a(med-jo/+) mice displayed thresholds that were comparable to wild-type littermates. The Scn8a(med-jo) allele was also able to rescue the premature lethality of Scn1a(+/-) mice and extend the lifespan of Scn1a(-/-) mutants. These results demonstrate that genetic interactions can alter seizure severity and support the hypothesis that genetic modifiers contribute to the clinical variability observed in SMEI and GEFS+.
Martin
Melinda S
MS
Department of Human Genetics, Emory University, Atlanta, GA 30322, USA.
Tang
Bin
B
Papale
Ligia A
LA
Yu
Frank H
FH
Catterall
William A
WA
Escayg
Andrew
A
D000818:Animals; D001483:Base Sequence; D017931:DNA Primers / Q000235:genetics; D004195:Disease Models, Animal; D004831:Epilepsies, Myoclonic / Q000235:genetics* / Q000503:physiopathology; D005260:Female; D005804:Genes, Lethal; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007223:Infant; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D009154:Mutation; D062550:NAV1.1 Voltage-Gated Sodium Channel; D062557:NAV1.6 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000235:genetics* / Q000502:physiology; D010641:Phenotype; D012640:Seizures / Q000235:genetics / Q000503:physiopathology; D015222:Sodium Channels / Q000172:deficiency / Q000235:genetics* / Q000502:physiology
D017931:DNA Primers; D062550:NAV1.1 Voltage-Gated Sodium Channel; D062557:NAV1.6 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; C568242:SCN1A protein, human; C100681:SCN8A protein, human; C568249:Scn1a protein, mouse; C491046:Scn8a protein, mouse; D015222:Sodium Channels