The Role of THAP1 in Dystonia

描述(申请人提供)：肌张力障碍被定义为持续肌肉收缩的综合征，经常导致扭转和重复运动，或不正常的姿势。最近，基因THAP1的突变被确定为阿米什-门诺派人群中DTY6肌张力障碍的原因。对散发性和家族性(主要是成人起病的)原发性肌张力障碍患者的高通量随访筛查显示，不同种类的THAP1序列变异与不同人群中不同的解剖模式和原发性肌张力障碍的发病年龄有关。显然，THAP1似乎是迄今为止发现的成人起病的原发性肌张力障碍最重要的遗传病因。THAP1编码转录因子THAP1。使用一个包含成人起病的原发性肌张力障碍患者的DNA和淋巴细胞的大型生物库，我们将检查肌张力障碍风险与最近发现的THAP1序列变体之间的关联，并询问THAP1的拷贝数以及额外的编码和非编码序列变体。利用淋巴母细胞系、转基因细胞系和基因表达谱，我们将确定单个THAP1序列变异对THAP1表达和功能的影响。这项工作将在基因测试和咨询的背景下产生直接的临床影响。最近在人类和动物模型上的研究强烈表明，DYT1、DYT6和其他形式的肌张力障碍可能是神经发育障碍。转录失调和小脑输出异常一直是肌张力障碍研究的另一个主要主题。因此，我们将检测THAP1蛋白和转录本在神经组织中的发育表达，并通过敲除THAP1基因来建立DYT6肌张力障碍小鼠模型。初步数据表明，THAP1在发育中的浦肯野细胞中高水平表达。对Thap1-KO小鼠的形态研究将使我们能够检验THAP1对于小脑浦肯野细胞的正常形态发育是必不可少的假设。此外，CHIP-SEQ和CHIP-CHIP实验的数据将被合并，以便在小脑皮质成熟期间确定体内THAP1 DNA结合部位。这些实验的完成将揭示肌张力障碍相关的细胞网络，指出原发性肌张力障碍的候选基因，并确定治疗肌张力障碍的分子靶点。 公共卫生意义：肌张力障碍是一种常见的神经系统疾病，表现为肌肉长期收缩，导致面部、颈部、躯干和四肢姿势异常。THAP1基因的突变会导致儿童和成年人的肌张力障碍。我们的研究将试图确定THAP1突变是如何导致肌张力障碍的发展的。

DESCRIPTION (provided by applicant): Dystonia has been defined as a syndrome of sustained muscle contractions, frequently causing twisting and repetitive movements, or abnormal postures. Recently, a mutation in the gene THAP1 was identified as the cause of DTY6 dystonia in Amish-Mennonites. Follow-up high-throughput screening of patients with sporadic and familial, mainly adult-onset, primary dystonia showed that a diverse assortment of THAP1 sequence variants is associated with varied anatomical patterns and onset ages of primary dystonia in diverse populations. Clearly, THAP1 appears to be the most important genetic etiology for adult-onset primary dystonia identified to date. THAP1 encodes the transcription factor THAP1. Using a large biorepository containing DNA and lymphocytes from subjects with adult-onset primary dystonia, we will examine associations between dystonia risk and recently identified THAP1 sequence variants, and interrogate THAP1 for copy number and additional coding and non-coding sequence variants. Using lymphoblastoid cell lines, transfected cell lines and gene expression profiling, we will determine the effects of individual THAP1 sequence variants on THAP1 expression and function. This work will have immediate clinical ramifications in the context of genetic testing and counseling. Recent studies in humans and animal models strongly suggest that DYT1, DYT6 and other forms of dystonia may be neurodevelopmental disorders. Transcriptional dysregulation and abnormal cerebellar output have been other major themes in dystonia research. Accordingly, we will examine the developmental expression of THAP1 protein and transcript in neural tissues and generate a model of DYT6 dystonia by knocking-out the Thap1 gene in mice. Preliminary data indicates that THAP1 is expressed at high levels in developing Purkinje cells. Morphological studies in Thap1-KO mice will allow us to test the hypothesis that THAP1 is essential for the normal morphological development of cerebellar Purkinje cells. In addition, data from ChIP-Seq and ChIP-chip experiments will be merged in order to identify THAP1 DNA binding sites in vivo during the maturation of cerebellar cortex. Completion of these experiments will unveil dystonia-associated cellular networks, point out candidate genes for primary dystonia and define molecular targets for the treatment of dystonia. PUBLIC HEALTH RELEVANCE: Dystonia is a common disorder of the nervous system that manifests as prolonged muscle contractions leading to abnormal postures of the face, neck, trunk and limbs. Mutations in the THAP1 gene cause dystonia in children and adults. Our research will attempt to determine exactly how THAP1 mutations lead to the development of dystonia.