Role of DYT1 Mutation in Dystonia

描述(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，有30-40%的外显率。DYT1突变是Torsin A的羧基末端附近的Gag缺失，目前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突变一起作用，才能导致肌张力障碍表型。为了确定DYT1突变在产生肌张力障碍表型中的作用，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。这些小鼠还将受到多巴胺的阻断，以调查环境应激在产生肌张力障碍表型中的作用。为了确定DYT1突变的基底节表达是否足以形成肌张力障碍表型，小鼠将接受纹状体内注射表达野生型或突变型Torsin A的病毒载体。注射的小鼠将通过高效液相色谱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.