Letter abstract

Nature Genetics 39, 776 - 780 (2007)
Published online: 7 May 2007 | doi:10.1038/ng2040

Mutation of RRM2B, encoding p53-controlled ribonucleotide reductase (p53R2), causes severe mitochondrial DNA depletion

Alice Bourdon1, Limor Minai1, Valérie Serre1,2, Jean-Philippe Jais3, Emmanuelle Sarzi1, Sophie Aubert1, Dominique Chrétien1, Pascale de Lonlay1, Véronique Paquis-Flucklinger4, Hirofumi Arakawa5, Yusuke Nakamura5, Arnold Munnich1 & Agnès Rötig1


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.

  1. Institut national de la santé et de la recherche médicale U781 and Service de Génétique, Hôpital Necker-Enfants Malades, 149 rue de Sèvres, 75015 Paris, France.
  2. Université Paris 7, 2 Place Jussieu, 75005 Paris, France.
  3. Service de biostatistique et Informatique Médicale Université René Descartes, Faculté de Médecine, Hôpital Necker-Enfants Malades, 149 rue de Sèvres, 75015 Paris, France.
  4. Department of Medical Genetics, Archet 2 Hospital, 151 Route St Antoine de Ginestière, 06107 Nice, France.
  5. Human Genome Center, Institute of Medical Science, University of Tokyo, 4-6-1 Shirikanedai, Minato-ku, Tokyo 108-8639, Japan.

Correspondence to: Agnès Rötig1 e-mail: roetig@necker.fr


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