A Mouse Model for a Dominant, Adult-Onset Ataxia (pilot)

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We have identified a phenotypic deviant within our CSU mouse colony that shows an adult-onset, progressive ataxia. Breeding analysis of this deviant strain (BxR23) suggests that the underlying cause of this ataxia is a Mendelian trait, transmitted in an autosomal dominant manner. Differences in severity of the phenotype between homozygotes and heterozygotes, however, suggest that the trait is incompletely dominant. We hypothesize that the mutation responsible for this trait resides in an as yet uncharacterized mouse gene. An alternative hypothesis is>that the mutation resides in a mouse gene that has been previously characterized. We are attempting to distinguish these alternatives by simultaneously mapping the mutation within the mouse genome through linkage analysis and developing mutation-detection assays for several candidate mouse genes. Necropsies of affected BxR23 mice have failed to identify a clear physiological basis for the ataxic phenotype, so a genetic approach is clearly the best way to characterize this disorder. We also propose to further document the onset and progression of the ataxia through standard observation methods such as the rotarod test and stride length measurements. In this way, a quantitative measure of phenotypic difference between homozygotes and heterozygotes can be attained. Although there are dozens of human ataxia syndromes caused by autosomal dominant mutations, there are no known mouse models of dominant ataxias. The BxR23 mouse may prove to be a useful model for studying the development of adult-onset, progressive ataxias in humans. Neurodegenerative diseases exact an enormous toll on the aging human population. Many of these diseases are inherited in an autosomal dominant fashion. Mouse models for these diseases, like the BxR23 mouse strain, are valuable tools in understanding the molecular and biochemical basis of human neurodegenerative disorders.