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- Title
Mutation of RRM2B, encoding p53-controlled ribonucleotide reductase (p53R2), causes severe mitochondrial DNA depletion.
- Authors
Bourdon, Alice; Minai, Limor; Serre, Valérie; Jais, Jean-Philippe; Sarzi, Emmanuelle; Aubert, Sophie; Chrétien, Dominique; de Lonlay, Pascale; Paquis-Flucklinger, Véronique; Arakawa, Hirofumi; Nakamura, Yusuke; Munnich, Arnold; Rötig, Agnès
- 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.
- Publication
Nature genetics, 2007, Vol 39, Issue 6, p776
- ISSN
1061-4036
- Publication type
Journal Article
- DOI
10.1038/ng2040