Genetic Studies of Neurologic and Dementing Disorders

神经系统和痴呆症的遗传学研究

• 批准号: 8958801
• 负责人: Thomas Dwight Bird
• 金额: --
• 依托单位: VA PUGET SOUND HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-10-01 至 2017-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8958801
• 关键词: Address; Affect; Aging; Amino Acid Sequence; Ataxia; Benign; Bioinformatics; Candidate Disease Gene; Categories; Charcot-Marie-Tooth Disease; Chromosome Mapping; Classification; Clinic; Clinical; Cloning; Complex; Copy Number Polymorphism; DNA; Dementia; Development; Diagnosis; Diagnostic; Disease; Dyskinetic syndrome; Equipment; Evaluation; Facial Myokymias; Familial Dementias; Family; Family member; Genes; Genetic Heterogeneity; Genetic study; Genome; Genomic Segment; Genomic approach; Genomics; Genotype; Goals; Health; Hereditary Disease; Hereditary Spastic Paraplegia; Human Genome Project; In Vitro; Individual; Inherited; Inherited Spinocerebellar Degenerations; Intervention; Knowledge; Lead; Light; Link; Location; Maintenance; Massive Parallel Sequencing; Medical; Mission; Molecular; Movement Disorders; Mutation; Myopathy; Nerve Degeneration; Nervous system structure; Neurodegenerative Disorders; Neurologic; Neuromuscular Diseases; Neuropathy; Open Reading Frames; Parkinsonian Disorders; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Peptide Sequence Determination; Phenotype; Population; Preventive; Process; Proteins; Research; Research Project Grants; Resolution; SNP array; Sampling; Spastic Paraplegia; Spinocerebellar Ataxias; System; Techniques; Technology; Testing; Validation; Variant; Veterans; analytical method; base; clinical investigation; clinical phenotype; cytopenia; diagnostic accuracy; disease-causing mutation; disorder prevention; disorder subtype; exome; exome sequencing; fascinate; gene discovery; gene function; gene product; genetic linkage analysis; genome-wide; genome-wide linkage; identity by descent; improved; innovation; interest; mutant; nervous system disorder; neurogenetics; next generation; non-alzheimer dementia; novel; novel strategies; positional cloning; programs; protein protein interaction; sample collection; spasticity; success; targeted sequencing

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.

描述（由申请人提供）： 这项研究的这些目标是确定导致五类遗传的孟德尔神经退行性疾病的突变（痉挛性截瘫，神经肌肉疾病，运动​​障碍，共济失调和非alzheimer痴呆症），并研究如何导致这些突变导致疾病。在过去的5年中，基因发现方法从基于链接分析的位置克隆转变为突变克隆，这是通过技术和分析设备进行了大规模平行的DNA测序的。这种新方法还依赖于人类基因组项目的成功，该项目提供了一个模板，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，因此该研究的重点是基因组的完整蛋白质编码区“外显子”。突变克隆的挑战是在单个外部的数千种良性蛋白改变变化的背景下确定致病性突变。所提出的方法结合了链接或逐个状态（IBD）分析，以识别所有受影响家庭成员共享的基因组区域和几个受影响亲戚的外显子组测序，以识别其在IBD地区共享的变体。生物信息学的进步提供了 逐步过滤方法选择可能进一步研究的可能的致病变异。单个家族中疾病的变体的cosegregation和突变的鉴定 其他家庭中的相同基因提供了该基因负责该疾病的验证。在可能的情况下，将进行有关突变对基因功能的影响的体外研究。 该研究利用了许多在过去25年中确定，广泛表征和扩展的许多家庭的大量样品。持续主题应计为拟议研究的统一特征。确定了新的疾病，为疾病验证而开发了受试者面板，并且可以确定基因型/表型相关性。除了基因发现对患有特定疾病的患者的影响之外，每个新基因还有助于我们理解与维持神经系统系统和神经变性途径有关的复杂蛋白质 - 蛋白质相互作用。这项研究的发现将是系统诊断方法以及最终治疗和预防这些疾病的重要组成部分。