Identification of a gene causing human cytochrome c oxidase deficiency by integrative genomics
Identification of a gene causing human cytochrome c oxidase deficiency by integrative genomics
复制标题
DOI：
10.1073/pnas.242716699
复制
发表时间：
2003-01-21
影响因子：
11.1
通讯作者：
Lander, ES
中科院分区：
文献类型：
--
作者：
Mootha, VK;Lepage, P;Lander, ES
识别导致人类疾病的基因需要将基因位置信息与生物功能线索结合起来。最近可用的RNA和蛋白质表达全基因组数据集为功能洞察提供了强大的新来源。在这里，我们通过使用这些数据集来识别导致Leigh综合征，法加型（LSFC）的基因，说明这些数据集如何能够加速疾病基因的发现。220111)，一种人类细胞色素c氧化酶缺陷，映射到染色体2p16-21。利用四个公开的RNA表达数据集，我们为所有人类基因分配了一个“分数”，反映了它们在RNA表达谱上与已知线粒体基因的相似性。通过对细胞器蛋白质组学的大规模调查，我们同样根据蛋白质产物与线粒体相关的可能性对人类基因进行了分类。通过将这些信息与相关基因组区域交叉，我们确定了一个明确的候选基因LRPPRC。重测序在两个独立的单倍型上发现了两个突变，为LRPPRC确实导致LSFC提供了明确的遗传证据。LRPPRC编码一种可能参与mtDNA转录加工的mrna结合蛋白，提示线粒体病理生理的另一种机制。整合不同基因组信息的类似策略同样可以应用于其他疾病途径，并将随着多样化、功能性基因组数据的日益丰富而变得越来越强大。
Identifying the genes responsible for human diseases requires combining information about gene position with clues about biological function. The recent availability of whole-genome data sets of RNA and protein expression provides powerful new sources of functional insight. Here we illustrate how such data sets can expedite disease-gene discovery, by using them to identify the gene causing Leigh syndrome, French-Canadian type (LSFC, Online Mendelian Inheritance in Man no. 220111), a human cytochrome c oxidase deficiency that maps to chromosome 2p16-21. Using four public RNA expression data sets, we assigned to all human genes a "score" reflecting their similarity in RNA-expression profiles to known mitochondrial genes. Using a large survey of organellar proteomics, we similarly classified human genes according to the likelihood of their protein product being associated with the mitochondrion. By intersecting this information with the relevant genomic region, we identified a single clear candidate gene, LRPPRC. Resequencing identified two mutations on two independent haplotypes, providing definitive genetic proof that LRPPRC indeed causes LSFC. LRPPRC encodes an mRNA-binding protein likely involved with mtDNA transcript processing, suggesting an additional mechanism of mitochondrial pathophysiology. Similar strategies to integrate diverse genomic information can be applied likewise to other disease pathways and will become increasingly powerful with the growing wealth of diverse, functional genomics data.