Systematic identification of human mitochondrial disease genes through integrative genomics

Sarah Calvo, Mohit Jain, Xiaohui Xie, Sunil A. Sheth, Betty Chang, Olga A. Goldberger, Antonella Spinazzola, Massimo Zeviani, Steven A. Carr, Vamsi K. Mootha

Research output: Contribution to journalArticlepeer-review


The majority of inherited mitochondrial disorders are due to mutations not in the mitochondrial genome (mtDNA) but rather in the nuclear genes encoding proteins targeted to this organelle. Elucidation of the molecular basis for these disorders is limited because only half1,2 of the estimated 1,500 mitochondrial proteins3 have been identified. To systematically expand this catalog, we experimentally and computationally generated eight genome-scale data sets, each designed to provide clues as to mitochondrial localization: targeting sequence prediction, protein domain enrichment, presence of cis-regulatory motifs, yeast homology, ancestry, tandem-mass spectrometry, coexpression and transcriptional induction during mitochondrial biogenesis. Through an integrated analysis we expand the collection to 1,080 genes, which includes 368 novel predictions with a 10% estimated false prediction rate. By combining this expanded inventory with genetic intervals linked to disease, we have identified candidate genes for eight mitochondrial disorders, leading to the discovery of mutations in MPV17 that result in hepatic mtDNA depletion syndrome4. The integrative approach promises to better define the role of mitochondria in both rare and common human diseases.

Original languageEnglish
Pages (from-to)576-582
Number of pages7
JournalNature Genetics
Issue number5
Publication statusPublished - May 2006

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics


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