Genetic Movement Disorders: Etiologies and Pathogeneses

在这一应用中，我们建议将遗传运动障碍的分子病因确定为 向改进诊断、阐明病因和促进发展的努力迈出的重要一步 有针对性的治疗。这个项目研究的疾病类别，包括帕金森综合症， 共济失调、痉挛性截瘫和舞蹈性或肌张力障碍都是遗传异质性的，并且 还有更多的亚型有待发现。我们将通过三个具体目标实现我们的目标。 我们将：1)继续确定和描述有遗传缺陷的个人和家庭的特征 运动障碍；2)利用基因定位和分子生物学的进展 发现和验证运动障碍新基因的技术和生物信息学；以及3) 评估致病变异对基因功能和临床表现的影响。我们在此基础上 研究人员与他们的神经学和分子遗传学之间建立了协同合作 并利用已确定的两大样本集合的宝贵资源， 具有广泛的特征，并延续了30多年(神经遗传学和帕金森病 存储库)。 从位置克隆到突变克隆的转变是由于 大规模并行DNA测序和人类基因组计划的成功提供了 用来比较从任何个体获得的序列的模板。因为绝大多数人 的遗传性疾病是由影响蛋白质序列的突变引起的，这项研究重点是 “外显子组”，基因组的集体蛋白质编码区。突变克隆的挑战是 在数千种良性蛋白质变化的背景中鉴定致病突变 个体外星人。我们建议的方法结合了传统的连锁或血统身份(IBD) 确定所有受影响家庭成员共有的基因组区域的分析和外显子组测序 几个受影响的亲属，以确定他们在连锁/IBD区域共享的变异。统计学方面的进展 遗传学使在更小的家庭中进行此类研究成为可能，并提供了更强大的生物信息学 一种逐步筛选的方法，以选择可能的致病变异进行进一步研究。“种族隔离” 单家系致病变异和其他家系同一基因突变的鉴定 具有相同疾病的零星病例小组提供了对该基因负责的验证 疾病。然后，可以通过机制研究来研究疾病的发病机制。这种方法具有 导致了我们在解析遗传性神经疾病方面的一贯效率的记录。 为了举例说明，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 对患有某种疾病的患者的发现，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神经系统和通路的维持 神经退行性变。此外，从它们的生化途径和蛋白质复合体来看，每个新的 基因可以发现更多导致这种疾病的候选基因。这项研究的结果将是一个 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。

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.