Defining the genetic basis of human respiratory chain disease

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舞台。我们对这个细胞器的了解大部分来自于对线粒体呼吸链疾病（RCD）的研究。这种毁灭性的疾病是由于线粒体DNA或核DNA中的遗传缺陷导致线粒体呼吸链故障。几乎所有的器官系统都会受到影响。RCD影响估计1：5000的活产，并且是毁灭性的-诊断极其困难，需要多名医生的咨询和侵入性活检，目前没有有效的治疗方法。这些疾病中有一小部分是母系的，但绝大多数是由于核基因突变引起的，其中许多尚未被确定。我们的研究团队最近使用整合蛋白质组学来定义编码线粒体蛋白质组的~1100个核基因-这些基因代表了RCD候选基因的近乎全面的集合。在目前的应用中，我们组建了一个由线粒体医学、计算基因组学和大规模测序领域的领导者组成的团队，对一组约120名临床特征为RCD的患者中的所有约1100个核基因进行全面重测序。通过这个项目，我们解决了RCD的分子基础，为RCD建立了一个简单，全面的DNA诊断测试;并确定了许多新的线粒体疾病基因，这些基因将解锁线粒体生物学的新口袋。 公共卫生相关性：线粒体疾病是人类遗传性疾病中最大的一类，影响儿童和成人。我们将分析这些疾病患者的DNA，以发现其分子基础。这项研究的结果可能有助于我们更好地诊断和治疗这些毁灭性的疾病。

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 mitochondrial respiratory chain disease (RCD). This devastating disease is due to genetic defects in the mtDNA or the nuclear DNA that give rise to a malfunctioning mitochondrial respiratory chain. Virtually all organ systems can be affected. RCD 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 no effective therapies are available. A small fraction of these disorders are maternally, but the vast majority of these disorders are due to mutations in nuclear genes, many of which have yet to be identified. Our research team has recently used integrative proteomics to define the ~1100 nuclear genes that encode the mitochondrial proteome - these genes represent a near-comprehensive collection of candidate genes for RCD. In the current application we have assembled a team consisting of leaders in mitochondrial medicine, computational genomics, and large-scale sequencing, to comprehensively resequence all these ~1100 nuclear genes in a panel of ~120 patients with clinically characterized RCD. Through this project, we solve the molecular bases for RCD, establish a facile, comprehensive DNA diagnostic test for RCD; and identify scores of new mitochondrial disease genes that will unlock new pockets of mitochondrial biology. PUBLIC HEALTH RELEVANCE: Mitochondrial disorders comprise one of the largest classes of inherited human disease, affecting both children and adults. We will analyze the DNA of patients with such disorders to discover their molecular basis. The results of this study may help us better diagnose and treat these devastating diseases.