The Role of THAP1 in Dystonia

THAP1 在肌张力障碍中的作用

• 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
• 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

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一种持续肌肉收缩综合征，经常引起扭曲和重复运动，或异常姿势。最近，基因THAP1的突变被确定为阿米什-门诺派教徒DTY6肌张力障碍的原因。对散发性和家族性（主要为成人发病）原发性肌张力障碍患者的随访高通量筛查显示，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。利用一个包含成人发病原发性肌张力障碍患者DNA和淋巴细胞的大型生物库，我们将研究肌张力障碍风险与最近发现的THAP1序列变异之间的关系，并询问THAP1的拷贝数以及其他编码和非编码序列变异。利用淋巴母细胞样细胞系、转染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。这项工作将在基因检测和咨询方面产生直接的临床影响。最近的人类和动物模型研究强烈提示DYT1、DYT6等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另一个主要主题。因此，我们将检测THAP1蛋白在神经组织中的发育表达和转录，并通过敲除THAP1基因在小鼠中产生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。对THAP1 - ko小鼠的形态学研究将使我们能够验证THAP1对小脑浦肯野细胞的正常形态发育至关重要的假设。此外，我们将合并ChIP-Seq和ChIP-chip实验的数据，以鉴定小脑皮层成熟过程中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。