Creation of mouse models for DYT6 dystonia

描述(申请人提供)：原发性扭转肌张力障碍(PTDS)是一组以扭转肌肉收缩为特征的运动障碍，肌张力障碍是唯一的临床症状(震颤除外)，没有证据表明神经元变性或后天原因。DYT1、2、4、6、7、13和17等7个基因已被定位为原发性肌张力障碍的易感基因，然而直到最近，大多数早发性全身性肌张力障碍的遗传基础仍被确定，其中只有一个基因DYT1是由TOR1A基因的三个碱基杂合缺失引起的。由于创始人效应，这种突变约占德系犹太人早发性PTD病例的90%，但在非犹太人中所占比例不到50%。我们最近发现了一个新的早发性PTD基因THAP1，该基因突变导致DYT6肌张力障碍。在这项应用中，我们将产生高表达人THAP1wt或突变蛋白的转基因小鼠，并将产生一种thap1神经元特异性条件性基因敲除小鼠。我们将对这些小鼠进行研究，以确定THAP1基因产物的正常功能以及该病是由功能获得或丧失机制引起的。在这个项目中产生的所有小鼠都将接受神经学和运动表型的评估，并接受神经化学和神经病理学分析。针对DYT6肌张力障碍的小鼠模型的开发将有助于确定早发性PTD的共同机制，并为设计这些鲜为人知的致残性疾病的新疗法奠定基础。 公共卫生相关性：大多数原发性肌张力障碍(PTD)的遗传基础仍不清楚，其病理生理机制也知之甚少。治疗是不完整的，而且是经验性的。随着一种新的PTD基因的发现，我们现在可以制造出针对这种疾病的小鼠模型。这些模型的开发将提供一种独特的工具来阐明肌张力障碍的潜在机制，并为设计针对这些鲜为人知的致残性疾病的新疗法奠定基础。

DESCRIPTION (provided by applicant): Primary torsion dystonias (PTDs) are a group of movement disorders characterized by twisting muscle contractures, where dystonia is the only clinical sign (except for tremor) and there is no evidence of neuronal degeneration or an acquired cause. Seven genes have been mapped for primary dystonia including DYT1, 2, 4, 6, 7, 13 and 17, however until recently, the genetic basis for only one of these, DYT1, responsible for most cases of early onset generalized dystonia, has been identified and is caused by a heterozygous three basepair in-frame deletion in the TOR1A gene. This mutation accounts for about 90% of early onset PTD cases in the Ashkenazi Jewish population due to a founder effect but in the non-Jewish population it accounts for less than 50%. We have recently identified a new early onset PTD gene, THAP1, mutations in which cause DYT6 dystonia. In this application, we will generate overexpressing transgenic mice harboring the human THAP1 wt or mutant protein and will generate a Thap1 neuronal specific conditional knock-out mouse. We will study these mice to determine the normal function of the THAP1 gene product and whether the disease is caused by a gain or loss of function mechanism. All mice generated in this project will be evaluated for neurologic and motoric phenotypes and undergo neurochemical and neuropathological analyses. Development of mouse models specific for DYT6 dystonia will allow for the determination of common mechanisms among early onset PTDs and provide the foundation for devising novel treatments for these poorly understood and disabling diseases. PUBLIC HEALTH RELEVANCE: The genetic basis of most Primary torsin dystonias (PTD) remains unknown and the pathophysiological mechanisms are poorly understood. Treatment is incomplete and empiric. With the discovery of a new PTD gene we can now generate mouse models specific to this disorder. Development of these models will provide a unique tool to clarify the underlying mechanisms of dystonia and provide the foundation for devising novel treatments for these poorly understood and disabling diseases.