Human Mitochondrial Disease: From Novel Gene Variants to Causality and Function

人类线粒体疾病：从新基因变异到因果关系和功能

基本信息

批准号：
8083807
负责人：
Vamsi Krishna Mootha
金额：
$ 53.62万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-06-15 至 2015-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8083807
关键词：
Accounting Affect Aging Alleles Apoptosis Biochemical Biochemistry Biogenesis Biological Assay Biopsy Candidate Disease Gene Cataloging Catalogs Cells Childhood Clinical Collection Complementary DNA Complex Consultations Coupled DNA Data Defect Diabetes Mellitus Diagnosis Disease Energy Metabolism Equipment and supply inventories Etiology Exons Functional disorder Funding Genes Genetic Transcription Genetic Variation Genome Genomics Goals Growth Hereditary Disease Homeostasis Human Inborn Errors of Metabolism Incidence Inherited Interruption Ions Knock-out Lead Life Link Live Birth Maintenance Mass Spectrum Analysis Medical Methods Mind Mitochondria Mitochondrial DNA Mitochondrial Diseases Mitochondrial Proteins Modeling Molecular Molecular Diagnosis Morbidity - disease rate Mutation Myopathy National Human Genome Research Institute Nerve Degeneration Nuclear Organelles Orthologous Gene Oxidative Phosphorylation Pathogenesis Pathogenicity Pathway interactions Patients Phenotype Physicians Prevalence Proteins Proteome Proteomics RNA Interference Research Respiration Respiratory Chain Seizures Signal Transduction Staging Stroke Syndrome System Technology Testing Translations Variant Work Yeasts base body system deafness effective therapy functional gain gene discovery human disease improved infancy insight meetings mitochondrial genome mortality mutant next generation novel novel strategies protein complex stem young adult

项目摘要

DESCRIPTION (provided by applicant): The mitochondrion is the center stage for energy metabolism, apoptosis, signaling, and ion homeostasis. Much of what we know about this organelle comes from studying genetic disorders of the organelle. These are devastating disorders that are due to genetic defects in the mtDNA or the nuclear DNA that give rise to a malfunctioning mitochondrial respiratory chain, the core machinery for oxidative phosphorylation (OXPHOS). Virtually all organ systems can be affected. OXPHOS disease affects an estimated 1:5000 live births and is devastating - it is extremely difficult to diagnose, requiring consultation by multiple physicians and invasive biopsies, and at present, and no effective therapies are available. A small fraction of mitochondrial OXPHOS disorders are maternally inherited, but the vast majority are due to mutations in nuclear genes, many of which have yet to be identified. Our research team has recently used integrated proteomics to define the ~1100 nuclear genes that encode the mitochondrial proteome - these genes represent a near-comprehensive collection of candidate genes for OXPHOS disease. We are now applying next-generation sequencing technology to sequence all ~1100 nuclear genes in a panel of over 100 patients with clinical evidence of OXPHOS disease. In the proposed project, we plan to (1) begin with the gene variants we discover through medical next-generation sequencing and perform cDNA rescue studies to create an experimentally validated catalog of mitochondrial OXPHOS disease genes and then (2) assign novel, validated disease genes to specific steps in the mitochondrial pathway for OXPHOS biogenesis. Our work will capitalize on the rich set of new variants we are discovering through ARRA funded next generation medical sequencing. If successful, our work will improve our ability to establish molecular diagnoses in these crippling disorders. The genes and pathways we discover may shed insights into the pathogenesis of some very common diseases, such as neurodegeneration, diabetes, and infantile mortality, which may stem from dysfunction in this organelle. Finally, this project promises to have a valuable impact in fundamental biochemistry by revealing new proteins required for the assembly and biogenesis of the OXPHOS system. PUBLIC HEALTH RELEVANCE: The mitochondrial OXPHOS diseases collectively represent the most common inborn error of metabolism. The prevalence is estimated to be 1:5000 live births. These disorders can present in childhood or in young adulthood and are difficult to diagnose and manage, and no cures are available. The proposed project aims to help establish a validated collection of genes that underlie these disorders. The results will aid in the diagnosis and management of these devastating disorders.

描述（由申请人提供）：线粒体是能量代谢、细胞凋亡、信号传导和离子稳态的中心阶段。我们对这种细胞器的了解大部分来自于对细胞器遗传疾病的研究。这些是毁灭性的疾病，由线粒体 DNA 或核 DNA 的遗传缺陷引起，导致线粒体呼吸链（氧化磷酸化 (OXPHOS) 的核心机制）出现故障。几乎所有器官系统都会受到影响。 OXPHOS 疾病影响估计 1:5000 的活产，并且是毁灭性的 - 诊断极其困难，需要多位医生会诊和侵入性活检，目前还没有有效的治疗方法。一小部分线粒体 OXPHOS 疾病是母系遗传的，但绝大多数是由于核基因突变所致，其中许多突变尚未确定。我们的研究团队最近使用集成蛋白质组学来定义编码线粒体蛋白质组的约 1100 个核基因 - 这些基因代表了 OXPHOS 疾病候选基因的近乎全面的集合。我们现在正在应用新一代测序技术对 100 多名具有 OXPHOS 疾病临床证据的患者的全部约 1100 个核基因进行测序。在拟议的项目中，我们计划 (1) 从我们通过医学下一代测序发现的基因变异开始，进行 cDNA 拯救研究，以创建经过实验验证的线粒体 OXPHOS 疾病基因目录，然后 (2) 分配新的、经过验证的疾病OXPHOS 生物合成线粒体途径中特定步骤的基因。我们的工作将利用我们通过 ARRA 资助的下一代医学测序发现的丰富的新变异。如果成功，我们的工作将提高我们对这些严重疾病进行分子诊断的能力。我们发现的基因和通路可能有助于深入了解一些非常常见的疾病的发病机制，例如神经退行性疾病、糖尿病和婴儿死亡率，这些疾病可能源于该细胞器的功能障碍。最后，该项目有望通过揭示 OXPHOS 系统组装和生物发生所需的新蛋白质，对基础生物化学产生有价值的影响。公共卫生相关性：线粒体 OXPHOS 疾病共同代表了最常见的先天性代谢错误。活产率估计为 1:5000。这些疾病可能出现在儿童期或成年早期，难以诊断和治疗，而且无法治愈。拟议的项目旨在帮助建立这些疾病背后的经过验证的基因集合。结果将有助于诊断和治疗这些破坏性疾病。