title: Genetic modifiers affecting severity of epilepsy caused by mutation of sodium channel Scn2a.
abstract: Mutations in the voltage-gated sodium channels SCN 1 A and SCN 2 A are responsible for several types of human epilepsy. Variable expressivity among family members is a common feature of these inherited epilepsies, suggesting that genetic modifiers may influence the clinical manifestation of epilepsy. The transgenic mouse model Scn 2 a(Q 54) has an epilepsy phenotype as a result of a mutation in Scn 2 a that slows channel inactivation. The mice display progressive epilepsy that begins with short-duration partial seizures that appear to originate in the hippocampus. The partial seizures become more frequent and of longer duration with age and often induce secondary generalized seizures. Clinical severity of the Scn 2 a(Q 54) phenotype is influenced by genetic background. Congenic C57BL/6J.Q 54 mice exhibit decreased incidence of spontaneous seizures, delayed seizure onset, and longer survival in comparison with [C57BL/6J x SJL/J]F(1).Q 54 mice. This observation indicates that strain SJL/J carries dominant modifier alleles at one or more loci that determine the severity of the epilepsy phenotype. Genome-wide interval mapping in an N(2) backcross revealed two modifier loci on Chromosomes 11 and 19 that influence the clinical severity of of this sodium channel-induced epilepsy. Modifier genes affecting clinical severity in the Scn 2 a(Q 54) mouse model may contribute to the variable expressivity seen in epilepsy patients with sodium channel mutations.
authors.affiliation: Department of Human Genetics, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
authors.forename: Sarah K
authors.initials: SK
authors.lastname: Bergren
authors.forename: Shu
authors.initials: S
authors.lastname: Chen
authors.forename: Andrzej
authors.initials: A
authors.lastname: Galecki
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Kearney
mesh_terms: D000483:Alleles; D000818:Animals; D002874:Chromosome Mapping; D033481:Chromosomes, Mammalian / Q000235:genetics*; D019295:Computational Biology; D004827:Epilepsy / Q000235:genetics*; D005838:Genotype; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics*; D062551:NAV1.2 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010641:Phenotype; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D015222:Sodium Channels / Q000235:genetics*
chemical_list: D062551:NAV1.2 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; C568251:SCN2A protein, human; C000654500:Scn2a protein, mouse; D015222:Sodium Channels