Chromosomal mapping of genes for epilepsy in NER: A rat strain with tonic-clonic seizures

Purpose: NER is a mutant rat strain that exhibits spontaneous tonic-clonic convulsions accompanied by epileptic discharges on ictal EEG and serves as a model for generalized tonic-clonic seizures in humans. Our previous exper iments have suggested that a major autosomal recessive gene and several min or genes regulate the inheritance of tonic-clonic seizures in NER. The purp ose of this study was to confirm the mode of inheritance and to locate the causative genes for epilepsy in NER on the rat genetic map. Methods: We developed F1 hybrid (F1) and reciprocal backcross progenies of NER with a seizure-resistant strain, F344, and evaluated their seizure susc eptibility under tossing-stimulated and nonstimulated conditions. Backcross animals were genotyped using simple sequence length polymorphism markers f or polymerase chain reactions. Linkage between seizure susceptibility and m arker loci was analyzed by chi(2) statistic tests and by the computer progr ams MAPMAKER/EXP and MAPMAKER/QTL. Results: Under tossing-stimulating conditions, tonic-clonic seizures were p rovoked in 90% of NER and 66% of (F1 x NER) backcross animals, but no seizu res occurred in the F344, F1, or (F1 x F344) backcross animals. Routine mon itoring of nonstimulated animals revealed spontaneous tonic-clonic convulsi ons in 100% of NER and 64.2% of (F1 x NER) backcross animals, but no seizur es in F344 or F1. Gender effect on seizure susceptibility was negligible in (F1 x NER) backcross in both conditions. Preliminary genome-wide scanning and subsequent precise location of the causative genes revealed seizure sus ceptibility loci, designated Ner1 and Ner2, on rat chromosomes 1 acid 3, re spectively. Conclusions: Ner1 is a locus that controls the inheritance of spontaneous t onic-clonic seizures in an autosomal recessive mode, whereas Ner2 affects t he occurrence of tossing-induced seizures. Orthologous genes in the vicinit y of these loci may be related to epileptogenesis in other species, includi ng humans.