THE ROLE OF THE DYT1 MUTATION IN DYSTONIA

Massachusetts General Hospital, Boston MA

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Abstract

DESCRIPTION (provided by applicant): The most common cause of early onset dystonia is DYT1 dystonia. DYT1 dystonia is inherited in an autosomal dominant manner with 30-40% penetrance. The DYT1 mutation is a GAG deletion near the carboxy terminus of the protein, torsin A. At this time, the function of torsin A is unknown. The lack of phenotypic expression in 60% to70% of individuals with the DYT1 mutation indicates that secondary factors (environmental or genetic) must operate in conjunction with the DYT1 mutation to result in a dystonic phenotype. To determine the role of the DYT1 mutation in generating a dystonic phenotype, transgenic mice expressing either wild-type or mutant torsin A will be systemically examined for motor abnormalities. The mice will also be subject to dopamine blockade, to investigate the role of environmental stress in the generation of a dystonic phenotype. To determine if basal ganglia expression of the DYT1 mutation is sufficient for development of a dystonic phenotype, mice will undergo intrastriatal injection with a viral vector expressing either wild-type or mutant torsin A. The injected mice will be examined for changes in phenotype as well as for changes in dopaminergic transmission via HPLC.