E1 mice epilepsy shows genetic polymorphism for s-adenosyl-L-homocysteine hydrolase

E1 mice are an animal model of human epilepsy (idiopathic complex partial s eizures). We have previously demonstrated abrupt poly(A)(+) RNA expression in liver from 1-day-old El mouse [Mita et al., 1991. Devl. Brain Res. 64, 2 7-35]. In the present study, we constructed a cDNA library of the poly(A)() RNA. By analyzing cDNA clones and nucleotide sequences, we found a clone that was homologous to a rat gene of s-adenosyl-L-homocysteine hydrolase (E C 3.3.1.1.) (SAHH) (a key enzyme in the active methyl transfer pathway) and showed the gene polymorphism/RFLP(PstI) between the epileptic strain, E1, and the non-epileptic mother strain, ddY, as indicated in a gel electrophor esis by cleaving 2.6 kb with PstI into 1.9 kb and 0.7 kb fragment bands. F1 (E1 x ddY) showed the heterozygosity. An attempt to determine the mutation on the genomic SAHH gene in the E1 disclosed a single nucleotide polymorph ism indicated by a C --> T transition in the 8th intron, by which the PstI site was created. SAHH enzymatic activity in the liver in 1-day-old E1 mice was slight (approximately 10%), and in fact was significantly lower than t hat of the control ddY. Results suggested that the abrupt primary mRNA tran scribed on the SAHH gene in the liver of 1-day-old E1 mice was processed pa rtially or incompletely because of the presence of the point mutation in th e intron. Accordingly, poor energy supply by the insufficient SAHH enzymati c activity in the brain postnatally may be responsible for epileptogenesis in this animal model. It is concluded that a single nucleotide SAHH gene po lymorphism may be associated with epilepsy in El mice. (C) 2001 Elsevier Sc ience Ltd. All rights reserved.