MPV17 encodes an inner mitochondrial membrane protein and is mutated in infantile hepatic mitochondrial DNA depletion.

TitleMPV17 encodes an inner mitochondrial membrane protein and is mutated in infantile hepatic mitochondrial DNA depletion.
Publication TypeJournal Article
Year of Publication2006
AuthorsSpinazzola, A, Viscomi, C, Fernandez-Vizarra, E, Carrara, F, D'Adamo, P, Calvo, S, Marsano, RMassimilia, Donnini, C, Weiher, H, Strisciuglio, P, Parini, R, Sarzi, E, Chan, A, DiMauro, S, Rötig, A, Gasparini, P, Ferrero, I, Mootha, VK, Tiranti, V, Zeviani, M
JournalNat Genet
Volume38
Issue5
Pagination570-5
Date Published2006 May
ISSN1061-4036
KeywordsAmino Acid Sequence, Animals, Cells, Cultured, Chromosomes, Human, Pair 2, Cloning, Molecular, DNA, Mitochondrial, Female, Fluorescent Antibody Technique, Humans, Intracellular Membranes, Liver Diseases, Male, Membrane Proteins, Mice, Mitochondria, Molecular Sequence Data, Mutation, Pedigree, Syndrome
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.

DOI10.1038/ng1765
Alternate JournalNat. Genet.
Citation Key10.1038/ng1765
PubMed ID16582910
Grant ListGGP030039 / / Telethon / Italy
TGM03P12 / / Telethon / Italy
TGM06S01 / / Telethon / Italy