One in 17,000 individuals is afflicted with a genetic form of ataxia. Patients with dominant spinocerebellar ataxia (SCA) display adult-onset, motor coordination deficits that usually lead to death. Clinical signs, age of onset, and disease duration vary substantially both among and within families making the clinical classification of this group of diseases extremely difficult. Future classifications of the ataxias will be based on the gene affected. The genetic heterogeneity of the ataxias provides a unique opportunity to understand more about the pathology of neurodegenerative disease through the isolation and characterization of the different genes which can all lead to varying degrees of neuronal loss in the cerebellum, brain stem, and spinal tracts. Toward this goal, I have identified and collected a previously unreported 10 generation ataxia kindred and have shown that the gene involved in not SCA1, SCA2 or Machado Joseph Disease (MJD). The long term goal of this project is to identify and characterize this novel ataxia gene. Understanding the various molecular systems defects that cause ataxia will lead to a better understanding of the interdependence and functioning of the neuronal systems that degenerate during the SCA disease process.
The specific aims are: 1. To localize the Lincoln ataxia gene (L-SCA) to a specific chromosome by linkage analysis. 2. To construct a high resolution (1,2-centiMorgan cM) genetic map for the chromosomal region containing the Lincoln ataxia gene. DNA from L- SCA family members as well as the CEPH panel of reference families will be used. 3. Once the L-SCA sub region has been well defined genetically, the following strategies will be used to isolate the defective gene: A) A physical map will be constructed using pulsed-field gel electrophoresis (PFGE) blots probed with DNA markers that are very closely linked to the ataxia gene; B) Overlapping yeast artificial chromosome clones (a YAC contig) will be isolated for the ataxia gene sub region. Candidate genes will be selected from the DNA contained in the YAC contig and examined for their possible role in the disease process. At this stage, screening for the possible involvement of unstable trinucleotide repeats will be a top priority. 4. Initial characterization of the L-SCA gene. Once the L-SCA gene is identified, our efforts will be directed towards understanding its biology. The sequence of the L-SCA gene (genomic and cDNA) will be obtained which may provide important clues as to its function. If the mutation is variable in affected individuals, as is the CAG repeat length within the SCA-1 gene, the mutation in affected individuals will be correlated with age of onset and clinical features.
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