Creation of mouse models for DYT6 dystonia

描述（由申请人提供）：原发性扭转肌张力障碍（PTDs）是一组以扭转肌挛缩为特征的运动障碍，其中肌张力障碍是唯一的临床症状（震颤除外），没有神经变性或获得性原因的证据。有7个基因被定位为原发性肌张力障碍，包括DYT1、2、4、6、7、13和17，然而直到最近，其中只有DYT1的遗传基础被确定，DYT1是大多数早发性全身性肌张力障碍的原因，它是由TOR1A基因框内三个碱基对的杂合缺失引起的。由于奠基者效应，这种突变占德系犹太人早发性PTD病例的90%，但在非犹太人群中，这一比例不到50%。我们最近发现了一种新的早发性PTD基因THAP1，该基因突变可导致DYT6肌张力障碍。在这项应用中，我们将产生含有人类THAP1 wt或突变蛋白的过表达转基因小鼠，并将产生THAP1神经元特异性条件敲除小鼠。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，以及该疾病是由功能的获得还是丧失引起的机制。本项目产生的所有小鼠将进行神经和运动表型评估，并进行神经化学和神经病理分析。开发针对DYT6肌张力障碍的小鼠模型将有助于确定早发性PTDs的共同机制，并为设计针对这些知之甚少和致残疾病的新治疗方法提供基础。

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.