Genetic Studies of Neurologic and Dementing Disorders

描述(由申请人提供)： 这项研究的目标是确定导致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病)的突变，并调查这些突变是如何导致疾病的。在过去的5年里，基因发现的方法发生了根本性的转变，从基于连锁分析的位置克隆到突变克隆，这是由于执行大规模DNA平行测序的技术和分析设备实现的。这一新方法还依赖于人类基因组计划的成功，该计划提供了一个模板，可以与从任何个人获得的序列进行比较。由于绝大多数遗传性疾病是由影响蛋白质序列的突变引起的，因此本研究将重点放在基因组的完整蛋白质编码区--“外显子”上。突变克隆的挑战是在数以千计的良性蛋白质改变个体外显体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身份(IBD)分析来确定所有受影响的家庭成员共享的基因组区域，以及几个受影响的亲属的外显子组测序来确定他们在IBD区域共享的变异。生物信息学的进步提供了一种 采用逐步筛选的方法，筛选出可能的致病变异进行进一步研究。单家系致病突变的共分离及基因突变的鉴定 其他家族中的相同基因证实了该基因是导致这种疾病的原因。在可能的情况下，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年来从许多家庭收集的大量样本，这些样本被确定、广泛地表征和扩展。持续的受试者累积是拟议研究的一个统一特征；识别新的疾病，开发受试者小组用于疾病-基因验证，并可以确定基因型/表型相关性。除了为患有特定疾病的患者发现基因之外，每个新的基因都有助于我们理解复杂的蛋白质-蛋白质相互作用，这些复杂的蛋白质相互作用涉及维持神经系统和神经退化的途径。这项研究的结果将是诊断以及最终治疗和预防这些疾病的系统方法的重要组成部分。

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.