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Genetic Movement Disorders: Etiologies and Pathogeneses

遗传运动障碍：病因和发病机制

基本信息

批准号：
9858233
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
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-01-01 至 2021-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9858233
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

项目摘要

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.

在这个应用程序中，我们建议确定遗传运动障碍的分子病因作为一个