THE DYT1 MUTATION IN DYSTONIA

描述（由申请人提供）：早发性肌张力障碍最常见的原因是DYT1肌张力障碍。DYT1肌张力障碍以常染色体显性遗传，外显率为30-40%。DYT1突变是在蛋白质torsin a的羧基末端附近的GAG缺失，此时，torsin a的功能尚不清楚。60%到70%的DYT1突变个体缺乏表型表达，这表明次要因素（环境或遗传）必须与DYT1突变一起起作用，从而导致张力异常表型。为了确定DYT1突变在产生肌张力异常表型中的作用，将对表达野生型或突变型torsin a的转基因小鼠进行系统的运动异常检查。小鼠也将受到多巴胺阻断，以研究环境应激在产生张力障碍表型中的作用。为了确定DYT1突变的基底节区表达是否足以导致肌张力障碍表型的发展，将小鼠进行纹状体内注射表达野生型或突变型torsin a的病毒载体。注射后的小鼠将通过HPLC检测表型变化以及多巴胺能传递的变化。

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.