Heterozygous mutations of the voltage-gated sodium channel SCN8A are associated with spike-wave discharges and absence epilepsy in mice

Ligia A. Papale¹^,2^,, Barbara Beyer³^,, Julie M. Jones⁴, Lisa M. Sharkey⁴, Sergio Tufik², Michael Epstein¹, Verity A. Letts³, Miriam H. Meisler⁴, Wayne N. Frankel³^,* and Andrew Escayg¹

¹ Department of Human Genetics, Emory University, Atlanta, GA 30322, USA ² Department of Psychobiology, Universidade Federal de São Paulo, São Paulo, Brazil ³ The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA and ⁴ Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109-5618, USA

^* To whom correspondence should be addressed. Tel: +1 2072886354; Fax: +1 2072886757; Email: wayne.frankel{at}jax.org

Received January 9, 2009; Accepted February 16, 2009

In a chemical mutagenesis screen, we identified the novel Scn8a^8Jallele of the gene encoding the neuronal voltage-gated sodiumchannel Na_v1.6. The missense mutation V929F in this allele altersan evolutionarily conserved residue in the pore loop of domain2 of Na_v1.6. Electroencephalography (EEG) revealed well-definedspike-wave discharges (SWD), the hallmark of absence epilepsy,in Scn8a^8J heterozygotes and in heterozygotes for two classicalScn8a alleles, Scn8a^med (null) and Scn8a^med-jo (missense). Mousestrain background had a significant effect on SWD, with mutantson the C3HeB/FeJ strain showing a higher incidence than on C57BL/6J.The abnormal EEG patterns in heterozygous mutant mice and theinfluence of genetic background on SWD make SCN8A an attractivecandidate gene for common human absence epilepsy, a geneticallycomplex disorder.

The first two authors contributed equally to the study.

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Human Molecular Genetics

Heterozygous mutations of the voltage-gated sodium channel SCN8A are associated with spike-wave discharges and absence epilepsy in mice