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

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.

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Figure 1: Linkage analysis, selection of candidate genes and mutation analysis.
Figure 2: MPV17 transcript, gene organization and protein.
Figure 3: Complementation studies in Saccharomyces cerevisiae.
Figure 4: Mitochondrial localization of MPV17.
Figure 5: Mpv17 versus peroxisomal PMP70 immunostaining.
Figure 6: Characterization of Mpv17−/− mice.

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Acknowledgements

We are indebted to B. Geehan for revising the manuscript, E. Lamantea for technical assistance and L. Palmieri for critical discussion. This work was supported by Fondazione Telethon-Italy (grant GGP030039), Fondazione Pierfranco e Luisa Mariani and MITOCIRCLE and EUMITOCOMBAT network grants from the European Union Framework Program 6.

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Correspondence to Massimo Zeviani.

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Supplementary information

Supplementary Fig. 1

Clinical and molecular characterization of individuals with mutant MPV17. (PDF 101 kb)

Supplementary Fig. 2

Alkali treatment of mitochondrial membranes. (PDF 87 kb)

Supplementary Table 1

Strategy for site-directed mutagenesis. (PDF 40 kb)

Supplementary Table 2

Oligonucleotides used for DNA blot and real-time PCR analyses on mouse genome. (PDF 32 kb)

Supplementary Table 3

Strategy for nucleotide sequencing of the human MPV17 gene. (PDF 31 kb)

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Spinazzola, A., Viscomi, C., Fernandez-Vizarra, E. et al. MPV17 encodes an inner mitochondrial membrane protein and is mutated in infantile hepatic mitochondrial DNA depletion. Nat Genet 38, 570–575 (2006). https://doi.org/10.1038/ng1765

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