Degenerative ataxias are a group of neurological disorder associated with dysfunction of cerebellum and its connection. The clinical manifestations include progressive incoordination of movements and gait leading to complete disability and eventually to death. In humans, the prevalence of hereditary ataxias range from 6 to 20 cases for every 100,000 which is comparable to the prevalence of ALS or multiple sclerosis in the US. Rodent models of human ataxias have been limited to mice. The Shaker rat is a naturally occurring X- linked model for Purkinje cell degeneration in the Wistar Furth (WF) background. In contrast to most rodent models of human ataxias in which neuronal loss is not pronounced, the shaker rat progresses from a normal number of Purkinje cells at birth to almost complete loss at 1 year.
Three specific aims are proposed: We will fine-map the shaker locus using F2's from an intercross of WF shaker rates with wildtype Brown Norway rats. A panel of 44 genetic markers that distinguish WF and BN alleles, informative in this cross, has been established.
A second aim will identify the shaker mutation by RNA sequencing of shaker and wildtype RNAs isolated from pre-symptomatic and symptomatic cerebella.
The third aim will employ whole genome sequencing for the case that the shaker mutation does not cause reduced abundance of the shaker transcript or is intronic. The overall goal of this proposal is the identification of the first gene in the rat leading to cerebellar PC degeneration and the establishment of the rat as a model system in which to test novel treatment strategies.

Public Health Relevance

Hereditary ataxias, which include autosomal dominant, recessive and X-linked, are group of genetic disorders characterized by slow progressive incoordination of gait and movements. Mutations in many genes have been identified for autosomal dominant and recessive forms of hereditary ataxias. However, gene associated with X-linked ataxia or the mechanisms underlying the disease are not yet well understood. This grant proposes to (i) identify the gene responsible for ataxic phenotype in the shaker rat known to have acquired in X-linked recessive manner (ii) detect mutation in this disease gene.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Exploratory/Developmental Grants (R21)
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Genetics of Health and Disease Study Section (GHD)
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Gwinn, Katrina
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University of Utah
Schools of Medicine
Salt Lake City
United States
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Figueroa, Karla P; Paul, Sharan; Calì, Tito et al. (2016) Spontaneous shaker rat mutant - a new model for X-linked tremor/ataxia. Dis Model Mech 9:553-62
Neuenschwander, Annalese G; Thai, Khanh K; Figueroa, Karla P et al. (2014) Amyotrophic lateral sclerosis risk for spinocerebellar ataxia type 2 ATXN2 CAG repeat alleles: a meta-analysis. JAMA Neurol 71:1529-34
Ashizawa, Tetsuo; Figueroa, Karla P; Perlman, Susan L et al. (2013) Clinical characteristics of patients with spinocerebellar ataxias 1, 2, 3 and 6 in the US; a prospective observational study. Orphanet J Rare Dis 8:177