Detecting genes in new and old mouse models for epilepsy: a prospectus through the magnifying glass.
Various spontaneous mutants and natural strain variants for either generalized tonic-clonic seizures, or non-convulsive absence seizures have been described in mice and rats over the years. Convulsive seizure models are usually ascertained by mere visual observation, while finding the less noticeable seizures of absence models often requires proactive screening of existing mutants with other phenotypes. To date, molecular cloning technologies has elucidated the primary basis of most of the known single locus epilepsy mutants. Together with the 20 or so mouse knockouts with seizure-related phenotypes described to date, the frequency at which the mutants appear and diversity of the proteins involved would suggest that 1000 or more genes can be mutated to give rise to influence epilepsy phenotypes. As many of these genes will cluster into molecular, cellular and developmental pathways, their identification may be very important for better understanding epileptic mechanisms. With this perspective, the approaches taken towards positional cloning of mouse epilepsy mutations is illustrated by comparing and contrasting the different stages of gene identification in three different models with which this author has been fortunate enough to be intimately involved: slow-wave epilepsy (common gene symbol: swe, Chr 4); tottering (tg, Chr 8); and stargazer (stg, Chr 15). The comparatively sobering outlook for positional cloning of the more common genetically 'complex' epilepsies will also be discussed, as will more efficient new strategies for model screening and identifying the remaining 985 (or so) genes.
Frankel
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The Jackson Laboratory, Bar Harbor, ME 04609, USA.
D000818:Animals; D002874:Chromosome Mapping / Q000379:methods*; D003001:Cloning, Molecular / Q000379:methods*; D004195:Disease Models, Animal; D004827:Epilepsy / Q000235:genetics* / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics*; D010641:Phenotype; D019655:Quantitative Trait, Heritable; D051381:Rats