Abstracts

RATIONALE: Tottering (tg), lethargic (lh), and stargazer (stg) are mouse models of absence epilepsy caused by mutations in three distinct voltage dependent Ca2+ channel subunit genes (?1A, ?4, and ?2). The phenotypes of the mutants are similar and consist primarily of recessively inherited spike-wave seizures (5-7 Hz) and severe ataxia. Since wild type ?1A, ?4, and ?2 subunits associate at the molecular level to form functional multimeric Ca2+ channels in vivo, we hypothesized that the mutant loci would also interact if two or more were simultaneously present in the genome of one individual. The demonstration of this type of genetic contingency could provide important insight into the basic mechanisms of inherited epilepsy that would not be revealed by analysis of the tg, lh, and stg mutations separately. METHODS: PCR was used to genotype mice for the tg (leaner-allele), lh, and stg mutations. Phenotypes were characterized by visual observation, rotarod and swimming assays, video-EEG monitoring, and ethosuximide response. RESULTS: We generated mice that were heterozygous for one, two, or three of the tg, lh, and stg mutations in all possible combinations. Consistent with recessive inheritence, tg/+, lh/+, and stg/+ mice showed no ataxia or seizures. However, two of the double-heterozygote genotypes (tg,stg/+,+ and lh,stg/+,+) and the triple-heterozygote genotype (lh,stg,tg/+,+,+) exhibited frequent ethosuximide-responsive spike-wave seizures. CONCLUSIONS: We report the development of a new class of genetic models of human absence epilepsy. Poly-heterozygote mice are derived from existing single-gene models but incorporate the non-Mendelian inheritance patterns of polygenic models. Unlike homozygous lh/lh, stg/stg, and tg/tg mutants, the poly-heterozygote mice display seizures without ataxia or other defects and thus appear to more closely resemble typical human absence epilepsy. These results demonstrate for the first time that non-Mendelian idiopathic epilepsy can arise from the co-inheritance of additive or synergistic defects in a small number of genes, even though the effect of each individual mutation is subclinical.