Genetic Movement Disorders: Etiologies and Pathogeneses

遗传运动障碍：病因和发病机制

• 批准号: 10291787
• 负责人: CYRUS P ZABETIAN
• 金额: --
• 依托单位: VA PUGET SOUND HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-01-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10291787
• 关键词: Affect; Aging; Amino Acid Sequence; Ataxia; Benign; Biochemical Pathway; Bioinformatics; Biological; Birds; Candidate Disease Gene; Categories; Chorea; Chromosome Mapping; Clinical; Cloning; Collaborations; Collection; DNA; Data Set; Development; Diagnosis; Disease; Dystonia; Dystonic Disorder; Etiology; Evaluation; Family; Family member; Genes; Genetic; Genetic Diseases; Genetic Predisposition to Disease; Genetic Research; Genome; Genomic Segment; Genotype; Goals; Health; Hereditary Dystonia; Hereditary Spastic Paraplegia; Human Genome Project; Individual; Inheritance Patterns; Inherited; Intervention; Knowledge; Light; Link; Maintenance; Massive Parallel Sequencing; Mission; Molecular; Molecular Biology; Molecular Genetics; Movement; Movement Disorders; Mutation; Nerve Degeneration; Neurologic; Neurology; Open Reading Frames; Parkinson Disease; Parkinsonian Disorders; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Phenotype; Preventive; Productivity; Proteins; Registries; Research; Research Personnel; Research Project Grants; Research Proposals; Resolution; Resources; SNP array; Sampling; Spastic Paraplegia; Structure; Study models; System; Techniques; Technology; United States; Validation; Variant; Veterans; analytical method; base; clinical phenotype; cost; diagnostic accuracy; disease-causing mutation; disorder prevention; exome; exome sequencing; fascinate; gene discovery; gene function; gene product; genetic technology; identity by descent; improved; in silico; in vitro Model; interest; member; military veteran; mutant; nervous system disorder; neurogenetics; positional cloning; proband; protein complex; protein protein interaction; recruit; repository; research study; sample collection; spasticity; success; targeted treatment

In this application we propose to identify the molecular etiologies of genetic movement disorders as an important step towards improving diagnoses, elucidating pathogeneses, and facilitating efforts to develop targeted therapies. The categories of disease studied in this project, including parkinsonian syndromes, ataxias, spastic paraplegias, and choreiform or dystonic disorders, are all genetically heterogeneous and many more subtypes remain to be discovered. We will accomplish our goals through three specific aims. We will: 1) continue to ascertain and characterize individuals and families with genetically unattributed movement disorders; 2) take advantage of advances in gene localization and molecular biology technologies and bioinformatics to discover and validate new genes for movement disorders; and 3) evaluate the effects of pathogenic variants on gene function and clinical manifestations. We build on established synergistic collaborations between the Investigators and their neurology and molecular genetics colleagues, and leverage the invaluable resources of two large collections of samples ascertained, extensively characterized, and extended over 30 years (Neurogenetics and Parkinson's disease repositories). The transition from positional cloning to mutational cloning was made possible by the development of massively parallel DNA sequencing and the success of the Human Genome Project that provided a template against which to compare the sequences obtained from any individual. Because the great majority of genetic diseases are caused by mutations that affect the protein sequence, this research focuses on the “exome”, the collective protein-coding regions of the genome. The challenge of mutational cloning is to identify a pathogenic mutation in the background of thousands of benign protein changing variations in individual exomes. Our proposed approach combines traditional linkage or identity-by-descent (IBD) analysis to identify genomic regions shared by all affected family members and exome sequencing of several affected relatives to identify the variants they share in the linkage/IBD region. Advances in statistical genetics make it possible to perform such studies in smaller families and more powerful bioinformatics offer a stepwise filtering approach to select the likely pathogenic variants for further study. Cosegregation of the variant with disease in single families and identification of mutations in the same gene in other families and panels of sporadic cases with the same disorder provide validation that the gene is responsible for the disease. Disease pathogenesis can then be investigated through mechanistic studies. This approach has led to our documented record of consistent productivity in parsing genetic neurologic disorders. For illustration, we describe multiple disorders whose causative genes we recently discovered, including RAB39B- and ATP6AP2-related parkinsonian syndromes. Beyond the implication of gene discovery for patients who suffer from a particular disorder, each new gene contributes to our understanding of the complex protein-protein interactions involved in maintenance of the neurologic system and pathways of neurodegeneration. Furthermore, from their biochemical pathways and protein complexes each new gene can uncover additional candidate genes for the disorders. The findings of this research will be an important part of a systematic approach to diagnosis and eventual treatment and prevention of these diseases.

在本申请中，我们建议将遗传性运动障碍的分子病因学确定为 朝着改善诊断、阐明发病机制和促进发展努力迈出的重要一步 靶向治疗。该项目研究的疾病类别，包括帕金森综合症， 共济失调、痉挛性截瘫以及舞蹈样或肌张力障碍均具有遗传异质性，并且 还有更多亚型有待发现。我们将通过三个具体目标来实现我们的目标。 我们将： 1) 继续确定和表征具有未归因基因的个人和家庭 运动障碍； 2）利用基因定位和分子生物学的进步 发现和验证运动障碍新基因的技术和生物信息学；和 3) 评估致病变异对基因功能和临床表现的影响。我们建立在 研究人员与其神经病学和分子遗传学之间建立了协同合作 同事们，并利用已确定的两个大量样本集合的宝贵资源， 广泛表征，并延续了 30 多年（神经遗传学和帕金森病 存储库）。 从定位克隆到突变克隆的转变是由于以下技术的发展而实现的： 大规模并行 DNA 测序和人类基因组计划的成功提供了 与从任何个体获得的序列进行比较的模板。因为绝大多数 的遗传病是由影响蛋白质序列的突变引起的，本研究重点关注 “外显子组”，基因组的集体蛋白质编码区域。突变克隆的挑战是 在数以千计的良性蛋白质改变变异的背景下识别致病性突变 个体外显子组。我们提出的方法结合了传统的联系或血统身份（IBD） 分析以确定所有受影响的家庭成员共享的基因组区域以及外显子组测序 一些受影响的亲属以确定他们在连锁/IBD区域中共有的变异。统计方面的进展 遗传学使得在较小的家庭中进行此类研究成为可能，并且更强大的生物信息学提供了 逐步过滤方法来选择可能的致病变异以供进一步研究。共隔离 单个家庭中患有疾病的变异以及其他家庭中相同基因的突变鉴定 具有相同疾病的散发病例组验证了该基因负责 疾病。然后可以通过机制研究来研究疾病的发病机制。这种方法有 导致我们在解析遗传性神经系统疾病方面保持一致的生产力记录。 为了说明这一点，我们描述了我们最近发现的多种疾病的致病基因， 包括 RAB39B 和 ATP6AP2 相关的帕金森综合征。超越基因的含义 对于患有特定疾病的患者的发现，每个新基因都有助于我们的理解 涉及维持神经系统和通路的复杂蛋白质-蛋白质相互作用 神经退行性变。此外，从它们的生化途径和蛋白质复合物来看，每一个新的 基因可以发现疾病的其他候选基因。这项研究的结果将是 诊断、最终治疗和预防这些疾病的系统方法的重要组成部分 疾病。