THE ROLE OF THE DYT1 MUTATION IN DYSTONIA

描述（由申请人提供）：早发性肌张力障碍的最常见原因是DYT 1肌张力障碍。DYT 1肌张力障碍以常染色体显性方式遗传，外显率为30-40%。DYT 1突变是蛋白质扭转蛋白A羧基末端附近的GAG缺失。此时，扭转蛋白A的功能尚不清楚。在60%-70%的DYT 1突变个体中缺乏表型表达表明，次要因素（环境或遗传）必须与DYT 1突变共同作用，导致张力障碍表型。为了确定DYT 1突变在产生张力障碍表型中的作用，将系统检查表达野生型或突变体扭转蛋白A的转基因小鼠的运动异常。还将对小鼠进行多巴胺阻断，以研究环境应激在张力障碍表型产生中的作用。为了确定DYT 1突变的基底神经节表达是否足以发展张力障碍表型，小鼠将接受表达野生型或突变型扭转蛋白A的病毒载体的纹状体内注射。将通过HPLC检查注射小鼠的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.