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

Hum Mol Genet. 2009 May 1;18(9):1633-41. doi: 10.1093/hmg/ddp081. Epub 2009 Mar 2.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • Disease Models, Animal
  • Electrophysiology
  • Epilepsy, Absence / genetics*
  • Epilepsy, Absence / metabolism
  • Epilepsy, Absence / physiopathology*
  • Heterozygote
  • Humans
  • Mice
  • Mice, Inbred C3H
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Molecular Sequence Data
  • Mutation*
  • Mutation, Missense
  • NAV1.6 Voltage-Gated Sodium Channel
  • Nerve Tissue Proteins / genetics*
  • Nerve Tissue Proteins / metabolism
  • Phenotype
  • Sodium Channels / genetics*
  • Sodium Channels / metabolism

Substances

  • NAV1.6 Voltage-Gated Sodium Channel
  • Nerve Tissue Proteins
  • Scn8a protein, mouse
  • Sodium Channels