The Role of THAP1 in Dystonia

描述（由申请人提供）：肌张力障碍被定义为持续肌肉收缩的综合征，经常导致扭曲和重复运动或异常姿势。 最近，THAP 1基因突变被确定为Amish-Mennonites中DTY 6肌张力障碍的原因。 对散发性和家族性原发性肌张力障碍（主要为成人发病）患者的随访高通量筛选显示，THAP 1序列变体的多样性与不同人群中原发性肌张力障碍的不同解剖模式和发病年龄相关。 显然，THAP 1似乎是迄今为止确定的成人发病原发性肌张力障碍的最重要的遗传病因。 THAP 1编码转录因子THAP 1。使用一个大型生物储存库，其中含有成人原发性肌张力障碍受试者的DNA和淋巴细胞，我们将研究肌张力障碍风险与最近发现的THAP 1序列变异之间的关联，并询问THAP 1的拷贝数和其他编码和非编码序列变异。 使用淋巴母细胞系，转染细胞系和基因表达谱，我们将确定单个THAP 1序列变体对THAP 1表达和功能的影响。 这项工作将在基因检测和咨询方面产生直接的临床影响。 最近对人类和动物模型的研究强烈表明，DYT 1、DYT 6和其他形式的肌张力障碍可能是神经发育障碍。 转录失调和异常小脑输出一直是肌张力障碍研究的其他主要主题。 因此，我们将研究THAP 1蛋白和转录本在神经组织中的发育表达，并通过敲除小鼠中的Thap 1基因来产生DYT 6肌张力障碍模型。 初步数据表明THAP 1在发育中的浦肯野细胞中以高水平表达。 在Thap 1-KO小鼠的形态学研究将使我们能够测试的假设，THAP 1是必不可少的小脑浦肯野细胞的正常形态发育。 此外，来自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在体内鉴定THAP 1 DNA结合位点。 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。 公共卫生相关性：肌张力障碍是一种常见的神经系统疾病，表现为长时间的肌肉收缩，导致面部、颈部、躯干和四肢的异常姿势。THAP 1基因突变会导致儿童和成人肌张力障碍。 我们的研究将试图确定THAP 1突变如何导致肌张力障碍的发展。

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.