Human Molecular Genetics Advance Access published online on September 19, 2007
Human Molecular Genetics, doi:10.1093/hmg/ddm248
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The voltage-gated sodium channel Scn8a is a genetic modifier of Severe Myoclonic Epilepsy of Infancy
1 Department of Human Genetics, Emory University, Atlanta, Georgia 30322, USA 2 Department of Psychobiology, Universidade Federal de São Paulo, São Paulo, Brazil 3 Department of Pharmacology, University of Washington, Seattle, Washington 98195, USA
* Corresponding author: Andrew Escayg, Ph.D. Emory University Department of Human Genetics 615 Michael Street Whitehead Building, Suite 301 Atlanta, Georgia 30322 Telephone number (404) 712-8328 Fax number (404) 727-3949 E-mail: aescayg{at}genetics.emory.edu
Received July 5, 2007; Revised August 21, 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 in epilepsy has not been investigated. To determine the relationship between Scn8a dysfunction and seizure susceptibility, we examined the thresholds of two Scn8a mouse mutants, Scn8amedand Scn8amed-jo, to flurothyl- and kainic acid-induced seizures. Both mutants were more seizure resistant than wild-type littermates, suggesting that altered Scn8a function reduces neuronal excitability. To determine whether impaired Scn8a 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 supports the hypothesis that genetic modifiers contribute to the clinical variability observed in SMEI and GEFS+.
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