Genetic and Molecular Characterization of SCA26

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DESCRIPTION (provided by applicant): The autosomal dominant spinocerebellar ataxias (SCA) are a clinically and genetically heterogeneous group of neurodegenerative diseases. It is clear that a diverse of genes and mutational mechanisms can cause SCA, but the molecular process and mechanism for Purkinje cell degeneration that leads to SCA is still unknown. Further insights into SCA pathogenesis may come from more studies that have demonstrated that not all SCAs are due to expanded DNA repeats in novel genes. We recently identified a large family with a novel dominant ataxia, register as SCA26, and mapped the disease locus to 19p13.3. The long-range goal of this research is to expand our understanding of the pathogenesis of the hereditary ataxias, and specifically the basis for the nearly selective Purkinje cell degeneration. We hypothesize that SCA26 is caused by a mutation in a gene that is vital to neuron survival or specific function in the cerebellum, and have identified a few compelling candidate genes. The objective of this project is to refine the locus map by recruiting more family members, and by seeking a different founder haplotype from unrelated families, and to identify the gene and mutational basis by sequencing all coding regions of top candidate genes, and to survey the prevalence of SCA26. This project is significant because: 1) it will directly benefit ataxic patients by providing a new genetic test for diagnosis and genetic consulting; 2) it will provide a new model to study Purkinje cell and cerebellar degeneration in ataxia patients; 3) more broadly, it will establish a new point to inter-connect known factors together, and unveil new insights to delineate the common pathways involved in neurodegeneration or vital to neuron survival and function.