Scientific Publications

Systematic identification of human mitochondrial disease genes through integrative genomics.

Publication TypeJournal Article
AuthorsCalvo, S., Jain M., Xie X., Sheth SA, Chang B., Goldberger OA, Spinazzola A., Zeviani M., Carr SA, and Mootha VK
AbstractThe 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 half of the estimated 1,500 mitochondrial proteins 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 syndrome. The integrative approach promises to better define the role of mitochondria in both rare and common human diseases.
Year of Publication2006
JournalNature genetics
Volume38
Issue5
Pages576-82
Date Published (YYYY/MM/DD)2006/05/01
ISSN Number1061-4036
DOI10.1038/ng1776
PubMedhttp://www.ncbi.nlm.nih.gov/pubmed/16582907?dopt=Abstract