Abstract
Mitochondrial DNA (mtDNA) depletion syndrome (MDS; MIM 251880) is a prevalent cause of oxidative phosphorylation disorders characterized by a reduction in mtDNA copy number. The hitherto recognized disease mechanisms alter either mtDNA replication (POLG (ref. 1)) or the salvage pathway of mitochondrial deoxyribonucleosides 5′-triphosphates (dNTPs) for mtDNA synthesis (DGUOK (ref. 2), TK2 (ref. 3) and SUCLA2 (ref. 4)). A last gene, MPV17 (ref. 5), has no known function. Yet the majority of cases remain unexplained. Studying seven cases of profound mtDNA depletion (1–2% residual mtDNA in muscle) in four unrelated families, we have found nonsense, missense and splice-site mutations and in-frame deletions of the RRM2B gene, encoding the cytosolic p53-inducible ribonucleotide reductase small subunit. Accordingly, severe mtDNA depletion was found in various tissues of the Rrm2b−/− mouse. The mtDNA depletion triggered by p53R2 alterations in both human and mouse implies that p53R2 has a crucial role in dNTP supply for mtDNA synthesis.
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Acknowledgements
We thank T. Soussi for discussion and J. Bentata, B. Chabrol, C. Fallet-Bianco and J.M. Liet for referring the study subjects. This research was supported in part by the Association Française contre les Myopathies, Mitocircle European Union Project (contract number LSHB-CT-2004-005260), Eumitocombat within the European Union Sixth Framework Program for Research, Priority 1 'Life sciences, genomics and biotechnology for health' (contract number LSHM-CT-2004-503116) and the French Agence Nationale pour la Recherche.
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A.B. identified the p53R2 mutations and performed the protein blot and mtDNA quantification in mouse, L.M. performed protein blot analysis, V.S. performed the modeling of ribonucleotide reductase, J.-P.J. performed the linkage analysis using Merlin software, E.S. performed the mitochondrial DNA quantification, S.A. was in charge of cell culture, D.C. identified the respiratory chain enzyme activity, P.d.L. was responsible for clinical management of subjects 3, 4 and 7 and their diagnosis, V.P.-F. was responsible for clinical management of subject 7 and her diagnosis, H.A. and Y.N. produced the Rrm2b−/− mouse, A.M. was responsible for clinical management of subjects 1 and 2 and wrote the paper, and A.R. designed the project and wrote the paper.
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Supplementary information
Supplementary Fig. 1
Sequence analysis of the RRM2B gene. (PDF 17 kb)
Supplementary Fig. 2
Sequence alignment of p53R2 and R2 proteins from human and nonhuman sources. (PDF 6 kb)
Supplementary Fig. 3
Protein blot analysis of Bax and Bcl2 in subject and control cells. (PDF 12 kb)
Supplementary Table 1
Oligonucleotide primers. (PDF 3 kb)
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Bourdon, A., Minai, L., Serre, V. et al. Mutation of RRM2B, encoding p53-controlled ribonucleotide reductase (p53R2), causes severe mitochondrial DNA depletion. Nat Genet 39, 776–780 (2007). https://doi.org/10.1038/ng2040
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DOI: https://doi.org/10.1038/ng2040
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