The Role of THAP1 in Dystonia

THAP1 在肌张力障碍中的作用

基本信息

批准号：
8041487
负责人：
MARK S LEDOUX
金额：
$ 32.38万
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/8041487
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 Counseling DNA DNA Binding Data Defect Development Drug Formulations Dystonia Endothelial Cells Ethnic group European Evolution Exons Face Family Follow-Up Studies Frequencies Functional RNA Gene Expression Profiling Genes Genetic 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 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 racial and ethnic 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，经常引起扭转和重复运动，或异常姿势。最近，THAP1 基因的突变被确定为阿米什门诺派 DTY6 肌张力障碍的原因。对散发性和家族性（主要是成人发病）原发性肌张力障碍患者的后续高通量筛查表明，THAP1 序列变异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，THAP1 似乎是迄今为止确定的成人原发性肌张力障碍最重要的遗传病因。 THAP1 编码转录因子 THAP1。使用包含来自成人原发性肌张力障碍受试者的 DNA 和淋巴细胞的大型生物样本库，我们将检查肌张力障碍风险与最近发现的 THAP1 序列变异之间的关联，并询问 THAP1 的拷贝数和其他编码和非编码序列变异。使用类淋巴母细胞系、转染细胞系和基因表达谱，我们将确定各个 THAP1 序列变异对 THAP1 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 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是肌张力障碍研究的其他主要主题。因此，我们将检查神经组织中 THAP1 蛋白和转录物的发育表达，并通过敲除小鼠中的 Thap1 基因来生成 DYT6 肌张力障碍模型。初步数据表明 THAP1 在发育中的浦肯野细胞中高水平表达。 Thap1-KO 小鼠的形态学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至关重要的假设。此外，来自 ChIP-Seq 和 ChIP 芯片实验的数据将被合并，以便在小脑皮质成熟过程中识别体内 THAP1 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，并确定肌张力障碍治疗的分子靶点。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。 THAP1 基因突变会导致儿童和成人肌张力障碍。我们的研究将尝试确切地确定 THAP1 突变如何导致肌张力障碍的发生。