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

  • 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.

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Metadaten
Document Type:Article
Language:English
Author:Antonella Spinazzola, Carlo Viscomi, Erika Fernandez-Vizarra, Franco Carrara, Pio D'Adamo, Sarah Calvo, René Massimiliano Marsano, Claudia Donnini, Hans Weiher, Pietro Strisciuglio, Rossella Parini, Emmanuelle Sarzi, Alicia Chan, Salvatore DiMauro, Agnes Rötig, Paolo Gasparini, Iliana Ferrero, Vamsi K. Mootha, Valeria Tiranti, Massimo Zeviani
Parent Title (English):Nature Genetics
Volume:38
Issue:5
First Page:570
Last Page:575
ISSN:1061-4036
DOI:https://doi.org/10.1038/ng1765
Pubmed Id:http://www.ncbi.nlm.nih.gov/pubmed?term=16582910
Publisher:Nature Publishing Group
Date of first publication:2006/04/02
Departments, institutes and facilities:Fachbereich Angewandte Naturwissenschaften
Institut für funktionale Gen-Analytik (IFGA)
Dewey Decimal Classification (DDC):5 Naturwissenschaften und Mathematik / 57 Biowissenschaften; Biologie / 576 Genetik und Evolution
Entry in this database:2015/04/02