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.
MPV17 encodes an inner mitochondrial membrane protein and is mutated in infantile hepatic mitochondrial DNA depletion / Spinazzola A; Viscomi C; Fernandez-Vizarra E;Carrara F; D’Adamo P; Calvo S; Marsano RM; Donnini C; Weiher H; Strisciuglio P; Parini R; Sarzi E; Chan A; Dimauro S; Rotig A; Gasparini P; Ferrero I; Mootha VK; Tiranti V; Zeviani M. - In: NATURE GENETICS. - ISSN 1061-4036. - 38(2006), pp. 570-575. [10.1038/ng1765]