Human Molecular Genetics Advance Access originally published online on September 19, 2007
Human Molecular Genetics 2007 16(23):2892-2899; doi:10.1093/hmg/ddm248
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
The voltage-gated sodium channel Scn8a is a genetic modifier of severe myoclonic epilepsy of infancy
1 Department of Human Genetics, Emory University, Atlanta, GA 30322, USA, 2 Department of Psychobiology, Universidade Federal de São Paulo, São Paulo, Brazil and 3 Department of Pharmacology, University of Washington, Seattle, WA 98195, USA
* To whom correspondence should be addressed at: Department of Human Genetics, Emory University, 615 Michael Street, Whitehead Building, Suite 301, Atlanta, GA 30322. Tel: +1 4047128328; Fax: +1 4047273949; Email: aescayg{at}genetics.emory.edu
Received July 5, 2007; Accepted August 23, 2007
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 (Nav1.6) in epilepsy has not been investigated. To determine the relationship between Nav1.6 dysfunction and seizure susceptibility, we examined the thresholds of two Scn8a mouse mutants, Scn8amed and Scn8amed-jo, to flurothyl- and kainic acid (KA)-induced seizures. Both mutants were more seizure resistant than wild-type littermates, suggesting that altered Nav1.6 function reduces neuronal excitability. To determine whether impaired Nav1.6 function could ameliorate seizure severity in a mouse model of SMEI, we generated Scn1a+/–; Scn8amed-jo/+ double heterozygous mice. Unlike Scn1a+/– mice that are more susceptible to flurothyl-induced seizures, Scn1a+/–; Scn8amed-jo/+ mice displayed thresholds that were comparable to wild-type littermates. The Scn8amed-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+.