Genetic Studies of Neurologic and Dementing Disorders

描述（由申请人提供）： 本研究的目的是确定引起五类遗传性孟德尔神经退行性疾病（痉挛性截瘫，神经肌肉疾病，运动障碍，共济失调和非阿尔茨海默氏痴呆）的突变，并研究这些突变如何导致疾病。在过去的5年中，基因发现的方法发生了根本性的转变，从基于连锁分析的定位克隆到突变克隆，通过进行大规模并行DNA测序的技术和分析设备成为可能。这种新方法也依赖于人类基因组计划的成功，该计划提供了一个模板，可以比较从任何个体获得的序列。由于绝大多数遗传疾病是由影响蛋白质序列的突变引起的，因此这项研究集中在“外显子组”，即基因组的完整蛋白质编码区。突变克隆的挑战是在个体外显子组中数千种良性蛋白质改变变异的背景下识别致病突变。所提出的方法结合了连锁或血统同一性（IBD）分析，以确定所有受影响的家庭成员共享的基因组区域和几个受影响的亲属的外显子组测序，以确定他们在IBD区域共享的变体。生物信息学的进步提供了一个 逐步过滤方法，以选择可能的致病性变体进行进一步研究。在单个家庭中变异与疾病的共分离和在基因组中突变的鉴定 同一基因在其他家族中的存在证实了该基因是导致该疾病的原因。如有可能，将进行突变对基因功能影响的体外研究。 这项研究利用了过去25年来从许多家庭中确定的大量样本，广泛表征和扩展。持续的受试者增加是拟议研究的一个统一特征;新的疾病被确定，受试者小组被开发用于疾病基因验证，并且可以确定基因型/表型相关性。除了对患有特定疾病的患者的基因发现的意义之外，每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，这些蛋白质-蛋白质相互作用涉及神经系统的维持和神经变性的途径。这项研究的结果将成为系统诊断和最终治疗和预防这些疾病的重要组成部分。

DESCRIPTION (provided by applicant): These goals of this study are to identify the mutations that give rise to inherited Mendelian neurodegenerative disorders in five categories (spastic paraplegia, neuromuscular disorders, movement disorders, ataxia, and non-Alzheimer dementia) and to investigate how these mutations lead to disease. During the past 5 years, there has been a fundamental shift in the approach to gene discovery from linkage analysis-based positional cloning to mutational cloning, made possible by technologies and analysis equipment that perform massively parallel sequencing of DNA. This new approach also relies on 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 complete protein- coding region 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. The proposed approach combines 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 IBD region. Advances in bioinformatics offer a stepwise filtering approach to select the likely pathogenic variants to study further. Cosegregation of the variant with disease in single families and identification of mutations in the same gene in other families provide validation that the gene is responsible for the disease. In vitro studies of the effect of the mutation on the function of the gene will be done when possible. The research takes advantage of the large collection of samples from many families ascertained, extensively characterized, and extended over the past 25 years. Continued subject accrual is a unifying feature of the proposed research; new disorders are identified, panels of subjects are developed for disease-gene verification, and genotype/phenotype correlations can be determined. 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. The findings of this research will be an important part of a systematic approach to diagnosis and the eventual treatment and prevention of these diseases.