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

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

Research output: Contribution to journalArticle

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 hepatocerebral1 (OMIM 251880). Known mutant genes, including TK2 (ref. 2), SUCLA2 (ref. 3), DGUOK (ref. 4) and POLG5,6, account for only a fraction of MDDS cases7. 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 (ref. 8). We found disease-segregating mutations in three families with hepatocerebral MDDS and demonstrated that, contrary to the alleged peroxisomal localization of the MPV17 gene product9, 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.

Original languageEnglish
Pages (from-to)570-576
Number of pages7
JournalNature Genetics
Volume38
Issue number5
DOIs
Publication statusPublished - May 2006

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

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    Spinazzola, A., Viscomi, C., Fernandez-Vizarra, E., Carrara, F., D'Adamo, P., Calvo, S., Marsano, R. M., Donnini, C., Weiher, H., Strisciuglio, P., Parini, R., Sarzi, E., Chan, A., DiMauro, S., Rötig, A., Gasparini, P., Ferrero, I., Mootha, V. K., Tiranti, V., & Zeviani, M. (2006). MPV17 encodes an inner mitochondrial membrane protein and is mutated in infantile hepatic mitochondrial DNA depletion. Nature Genetics, 38(5), 570-576. https://doi.org/10.1038/ng1765