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Chromosomal Mapping of Genes for Epilepsy in NER: A Rat Strain with Tonic‐Clonic Seizures
Author(s) -
Maihara Toshiro,
Noda Atsushi,
Yamazoe Hiroshi,
Voigt Birger,
Kitada Kazuhiro,
Serikawa Tadao
Publication year - 2000
Publication title -
epilepsia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.687
H-Index - 191
eISSN - 1528-1167
pISSN - 0013-9580
DOI - 10.1111/j.1528-1157.2000.tb00276.x
Subject(s) - epilepsy , backcrossing , genetics , biology , ictal , gene , tonic (physiology) , neuroscience
Summary: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 experiments have suggested that a major autosomal recessive gene and several minor genes regulate the inheritance of tonic‐clonic seizures in NER. The purpose 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 back‐cross progenics of NER with a seizure‐resistant strain, F344, and evaluated their seizure susceptibility under tossing‐stimulated and nonstimulated conditions. Backcross animals were genotyped using simple sequence length polymorphism markers for polymerase chain reactions. Linkage between seizure susceptibility and marker loci was analyzed by χ 2 statistic tests and by the computer programs MAPMAKER/EXP and MAPMAKER/QTL. Results : Under tossing‐stimulating conditions, tonic‐clonic seizures were provoked in 90% of NER and 66% of (F1 × NER) backcross animals, but no seizures occurred in the F344, F1, or (F1 × F344) backcross animals. Routine monitoring of nonstimulated animals revealed spontaneous tonic‐clonic convulsions in 100% of NER and 64.2% of (F1 × NER) backcross animals, but no seizures in F344 or F1. Gender effect on seizure susceptibility was negligible in (F1 × NER) backcross in both conditions. Preliminary genome‐wide scanning and subsequent precise location of the causative genes revealed seizure susceptibility loci, designated Nerl and Ner2 , on rat chromosomes 1 and 3, respectively. Conclusions : Nerl is a locus that controls the inheritance of spontaneous tonic‐clonic seizures in an autosomal recessive mode, whereas Ner2 affects the occurrence of tossing‐induced seizures. Orthologous genes in the vicinity of these loci may be related to epileptogenesis in other species, including humans.