Creation of mouse models for DYT6 dystonia

描述（由申请方提供）：原发性扭转肌张力障碍（PTD）是一组以扭转肌肉挛缩为特征的运动障碍，其中肌张力障碍是唯一的临床体征（震颤除外），并且没有神经元变性或后天原因的证据。原发性肌张力障碍的7个基因已被定位，包括DYT 1、2、4、6、7、13和17，然而直到最近，这些基因中只有一个DYT 1的遗传基础被鉴定出来，并且是由TOR1A基因中杂合的3个碱基对框内缺失引起的，DYT 1是大多数早发性全身性肌张力障碍病例的原因。由于创始人效应，这种突变占德系犹太人群体中早发性PTD病例的约90%，但在非犹太人群体中占不到50%。我们最近发现了一种新的早发性PTD基因THAP 1突变，该突变导致DYT 6肌张力障碍。在本申请中，我们将产生携带人THAP 1 wt或突变蛋白的过表达转基因小鼠，并将产生Thap 1神经元特异性条件性敲除小鼠。我们将对这些小鼠进行研究，以确定THAP 1基因产物的正常功能以及该疾病是否由功能机制的获得或丧失引起。将对本项目中产生的所有小鼠进行神经和运动表型评价，并进行神经化学和神经病理学分析。DYT6肌张力障碍特异性小鼠模型的开发将允许确定早发性PTD中的共同机制，并为设计针对这些知之甚少和致残性疾病的新型治疗方法提供基础。 公共卫生相关性：大多数原发性扭转性肌张力障碍（PTD）的遗传基础仍然未知，其病理生理机制也知之甚少。治疗是不完整的和经验性的。随着新PTD基因的发现，我们现在可以生成针对这种疾病的小鼠模型。这些模型的开发将提供一个独特的工具，以澄清肌张力障碍的潜在机制，并为这些知之甚少和致残性疾病的新治疗方法的设计提供基础。

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.