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- Title
MPV17 encodes an inner mitochondrial membrane protein and is mutated in infantile hepatic mitochondrial DNA depletion.
- Authors
Spinazzola, Antonella; Viscomi, Carlo; Fernandez-Vizarra, Erika; Carrara, Franco; D'Adamo, Pio; Calvo, Sarah; Marsano, René Massimiliano; Donnini, Claudia; Weiher, Hans; Strisciuglio, Pietro; Parini, Rossella; Sarzi, Emmanuelle; Chan, Alicia; DiMauro, Salvatore; Rötig, Agnes; Gasparini, Paolo; Ferrero, Iliana; Mootha, Vamsi K; Tiranti, Valeria; Zeviani, Massimo
- Abstract
The mitochondrial (mt) DNA depletion syndromes (MDDS) are genetic disorders characterized by a severe, tissue-specific decrease of mtDNA copy number, leading to organ failure. There are two main clinical presentations: myopathic (OMIM 609560) and hepatocerebral (OMIM 251880). Known mutant genes, including TK2, SUCLA2, DGUOK and POLG, account for only a fraction of MDDS cases. We found a new locus for hepatocerebral MDDS on chromosome 2p21-23 and prioritized the genes on this locus using a new integrative genomics strategy. One of the top-scoring candidates was the human ortholog of the mouse kidney disease gene Mpv17. We found disease-segregating mutations in three families with hepatocerebral MDDS and demonstrated that, contrary to the alleged peroxisomal localization of the MPV17 gene product, MPV17 is a mitochondrial inner membrane protein, and its absence or malfunction causes oxidative phosphorylation (OXPHOS) failure and mtDNA depletion, not only in affected individuals but also in Mpv17-/- mice.
- Publication
Nature genetics, 2006, Vol 38, Issue 5, p570
- ISSN
1061-4036
- Publication type
Journal Article
- DOI
10.1038/ng1765