THE ROLE OF THE DYT1 MUTATION IN DYSTONIA

DYT1 突变在肌张力障碍中的作用

• 批准号: 7022189
• 负责人: NUTAN SHARMA
• 金额: $ 17.06万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-05-01 至 2008-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7022189
• 关键词: 3,4 dihydroxyphenylacetate; alpha synuclein; behavior test; dopamine; dopamine antagonists; dopamine receptor; dystonia; fluorescence resonance energy transfer; gene environment interaction; gene expression; gene mutation; genetically modified animals; high performance liquid chromatography; homovanillate; laboratory mouse; neurogenetics; neuropathology; neurotransmitter transport; phenotype; protein localization; transfection /expression vector; transport proteins

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.

描述（由申请人提供）：早期发作肌张力障碍的最常见原因是dyt1肌张力障碍。 DYT1肌张力障碍以常染色体显性遗传遗传，并具有30-40％的渗透率。 dyt1突变是蛋白质A. TorsinA的羧基末端附近的GAG缺失。目前，Torsin A的功能尚不清楚。在60％至70％的患有DYT1突变的个体中缺乏表型表达表明，次要因素（环境或遗传）必须与DYT1突变结合起作用，以导致肌张力型表型。为了确定Dyt1突变在产生肌张力型表型中的作用，将系统检查表达野生型或突变体torsin a的转基因小鼠，以发现运动异常。小鼠还将受到多巴胺封锁的影响，以研究环境应激在产生肌张力型表型中的作用。为了确定Dyt1突变的基底神经节表达是否足以发展肌张力型表型，小鼠将接受表达野生型或突变体Torsin的病毒载体进行纹状体注射A。将检查注射的小鼠的注射小鼠，以了解表型的变化以及通过HPLC透射的变化。