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，我们提出鉴定遗传性运动障碍的分子病因学作为一种治疗方法。 朝着改善诊断、阐明发病机制和促进发展努力迈出了重要一步 靶向治疗。在这个项目中研究的疾病类别，包括帕金森综合征， 共济失调、痉挛性截瘫和舞蹈样或肌张力障碍，都是遗传异质性的， 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）继续确定和定性个人和家庭的遗传原因不明 运动障碍; 2）利用基因定位和分子生物学的进展 技术和生物信息学，以发现和验证运动障碍的新基因;以及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 在研究者和他们的神经学和分子遗传学之间建立了协同合作 同事们，并利用两个大型样本收集的宝贵资源， 广泛表征，并延长超过30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过渡是由于 大规模并行DNA测序和人类基因组计划的成功， 用于比较从任何个体获得的序列的模板。因为绝大多数人 的遗传疾病是由影响蛋白质序列的突变引起的，这项研究的重点是 “外显子组”，基因组的集体蛋白质编码区。突变克隆的挑战在于 在数千种良性蛋白质改变变异的背景中识别致病突变， 单个exomes我们提出的方法结合了传统的连锁或身份的血统（IBD） 分析以确定所有受影响的家庭成员共有的基因组区域， 几个受影响的亲属，以确定他们在连锁/IBD区域共享的变异。统计方面的进展 遗传学使得在更小的家庭中进行这样的研究成为可能，更强大的生物信息学提供了 逐步过滤方法，以选择可能的致病性变体进行进一步研究。共分离 在单个家族中与疾病相关的变异和在其他家族中同一基因中的突变的鉴定， 一组具有相同疾病的散发病例证实了该基因是导致 疾病疾病的发病机制，然后可以通过机制研究。这种方法有 导致了我们在解析遗传性神经疾病方面的一致生产力的记录。 为了说明，我们描述了多种疾病，我们最近发现了其致病基因， 包括RAB 39 B和ATP 6AP 2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来说，每一个新基因都有助于我们理解 复杂的蛋白质-蛋白质相互作用参与维持神经系统和途径 神经退行性疾病此外，从它们的生化途径和蛋白质复合物中， 基因可以发现额外的候选基因的疾病。这项研究的结果将是一个 这是诊断和最终治疗以及预防这些疾病系统方法的重要组成部分， 疾病