MOLECULAR GENETICS OF DOPA-RESPONSIVE DYSTONIA

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This project is focused on locating the gene for "dopa-responsive dystonia" (DRD), an autosomal dominant disorder. This disorder is a distinct subset of childhood-onset, idiopathic torsion dystonia (ITD), but has several features that separate it from ITD. In some cases it may have features suggestive of cerebral palsy, before clinical progression should allow separation of the disorders. Analysis of two families suggests that adult onset parkinsonism may be the clinical phenotype of gene carriers who do not manifest dystonia in childhood. This finding may have clinical relevance in some cases of hereditary parkinsonism. We propose to do linkage analysis on "Family S," the largest known kindred affected with DRD, to identify a chromosomal region linked to DRD. We will then use saturation mapping with known markers in the region or develop new markers by selective cloning methods to further delimit an obligate genetic region (OGR) for the DRD gene. We can then test for genetic heterogeneity with other smaller DRD families. A physical map of the OGR will be constructed by techniques such as pulse field gel electrophoresis and chromosome "walking." Coding sequences will be identified by several cloning and hybridization strategies and "candidate regions" compared in DNA between normal and affected individuals in an attempt to identify the disease locus. Identification of the gene for DRD may allow better understanding of the biochemical defect in DRD. Improved diagnostic reliability in childhood dystonic conditions and some forms of adult-onset parkinsonism should be possible.