Abstracts

Mutations in the voltage-gated sodium channels [italic]SCN1A[/italic] and [italic]SCN2A[/italic] 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 [italic]Scn2a^Q54[/italic] has an epilepsy phenotype due to a mutation in [italic]Scn2a[/italic] 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 [italic]Scn2a^Q54[/italic] phenotype is influenced by genetic background. Congenic C57BL/6J.Q54 mice exhibit decreased incidence of spontaneous seizures, delayed seizure onset, and longer survival in comparison with [C57BL/6J x SJL/J]F1.Q54 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. To localize loci responsible for the strain difference in seizure susceptibility between B6.Q54 and F1.Q54 mice, we carried out a backcross of F1.Q54 mice to strain B6. Backcross progeny carrying the [italic]Scn2a^Q54[/italic] transgene were observed for 30 min at 3 and 6 weeks of age. Mice that exhibited one or more seizures during the 30 min observation were classified as susceptible and mice without seizures as resistant. A 20 cM resolution genome scan was carried out on 79 backcross DNAs, including 38 susceptible and 41 resistant. Association between genotypes and presence of epilepsy was analyzed by categorical trait interval mapping. An interval-specific congenic line carrying an SJL/J segment of chromosome 19 was used to confirm the mapping results and to generate interval-specific congenic lines for refining the map interval. Genome-wide interval mapping in an N2 backcross revealed 2 modifier loci that influence the clinical severity of of this sodium channel-induced epilepsy on chromosomes 11 and 19, designated [italic]Moe1[/italic] (Modifier of Epilepsy 1) and [italic]Moe2[/italic], respectively. The modified phenotype is conferred by an interval-specific congenic mouse strain that carries an SJL/J-derived segment of chromosome 19 spanning the [italic]Moe2 [/italic]region on a C57BL/6J background. We have further refined the map interval of [italic]Moe2[/italic] using interval-specific subcongenic lines. We have identified genetic modifiers that influence the age of onset and clinical severity of sodium channel-induced seizures in mice. Identification of epilepsy modifier loci that influence susceptibility and disease progression will provide insight into the molecular events of epileptogenesis, and may identify novel therapeutic targets for the treatment of human patients. (Supported by NIH NS046315 (JK); Claude Pepper Center Grant AG024824 (AG).)