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, Claudia; 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]

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

DONNINI, Claudia;
2006-01-01

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.
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, Claudia; 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]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11381/2404953
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