The Role of THAP1 in Dystonia

THAP1 在肌张力障碍中的作用

基本信息

批准号：
8131765
负责人：
MARK S LEDOUX
金额：
$ 31.73万
依托单位：
UNIVERSITY OF TENNESSEE HEALTH SCI CTR
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-08-20 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8131765
关键词：
Ablation Adult Affect Age of Onset Amish Animal Model Behavior Binding Sites Biological Models Biology Brain Candidate Disease Gene Caucasians Caucasoid Race Cell Cycle Progression Cell Line Cell Proliferation Cerebellar cortex structure Clinical Code Collection Computer Simulation DNA DNA Binding Data Defect Development Drug Formulations Dystonia Endothelial Cells Ethnic group European Evolution Exons Face Family Frequencies Functional RNA Gene Expression Profiling Genes Genetic Genetic Counseling Genetic Predisposition to Disease Genetic Variation Genetic screening method German population Guidelines Human Individual Knock-out Lead Limb structure Lymphocyte Modeling Molecular Molecular Biology Molecular Target Molecular and Cellular Biology Morphology Motor Movement Mus Muscle Contraction Mutation Neck Neurodevelopmental Disorder Neurons North America Output Pathway interactions Patients Pattern Persons Play Population Heterogeneity Posture Primary Dystonias Proteins Purkinje Cells Race Research Risk Role Screening procedure Structure Syndrome Testing Tissues Transcript Variant Work Zinc Fingers angiogenesis biobank developmental neurobiology early onset follow-up high throughput screening in vivo insertion/deletion mutation lymphoblastoid cell line nervous system disorder neurodevelopment pediatric dystonia postnatal protein expression public health relevance relating to nervous system research study transcription factor

项目摘要

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.

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，经常引起扭曲和重复运动或异常姿势。最近，基因THAP1中的突变被确定为阿米什群岛中dty6 dystonia的原因。随访对零星和家族性（主要是成人发作）患者的高通量筛查，原发性肌张力障碍表明，各种THAP1序列变体与多样化的解剖学模式和不同种群中原发性二甲替代的发病年龄有关。显然，THAP1似乎是迄今为止鉴定出的成人发作原发性肌张力障碍的最重要的遗传病因。 THAP1编码转录因子THAP1。我们使用含有成人发作原发性肌张力障碍受试者的DNA和淋巴细胞的大型生物措施，我们将研究肌张力障碍风险与最近确定的THAP1序列变体之间的关联，并询问THAP1对拷贝数和其他编码和其他编码和非编码序列变体的询问。使用淋巴母细胞系，转染的细胞系和基因表达分析，我们将确定单个THAP1序列变体对THAP1表达和功能的影响。这项工作将在基因检测和咨询的背景下立即产生临床影响。对人类和动物模型的最新研究强烈表明DYT1，DYT6和其他形式的肌张力障碍可能是神经发育障碍。转录失调和小脑异常的输出是肌张力障碍研究中的其他主要主题。因此，我们将检查THAP1蛋白和转录本在神经组织中的发育表达，并通过在小鼠中淘汰THAP1基因来产生DYT6肌张力障碍的模型。初步数据表明THAP1在发育中的Purkinje细胞中以高水平表达。在THAP1-KO小鼠中的形态学研究将使我们能够检验以下假设：THAP1对于小脑Purkinje细胞的正常形态发展至关重要。此外，将合并来自CHIP-SEQ和CHIP-CHIP实验的数据，以鉴定小脑皮层成熟过程中体内的THAP1 DNA结合位点。这些实验的完成将公布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，并定义用于治疗肌张力障碍的分子靶标。公共卫生相关性：肌张力障碍是神经系统的一种常见疾病，表现为长时间的肌肉收缩，导致面部，颈部，躯干和四肢异常姿势。 THAP1基因的突变导致儿童和成人的肌张力障碍。我们的研究将尝试确切确定THAP1突变如何导致肌张力障碍的发展。