title: Mutation of RRM2B, encoding p53-controlled ribonucleotide reductase (p53R2), causes severe mitochondrial DNA depletion.
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.
authors.affiliation: 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.
authors.forename: Alice
authors.initials: A
authors.lastname: Bourdon
authors.forename: Limor
authors.initials: L
authors.lastname: Minai
authors.forename: Valérie
authors.initials: V
authors.lastname: Serre
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Jais
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Sarzi
authors.forename: Sophie
authors.initials: S
authors.lastname: Aubert
authors.forename: Dominique
authors.initials: D
authors.lastname: Chrétien
authors.forename: Pascale
authors.initials: P
authors.lastname: de Lonlay
authors.forename: Véronique
authors.initials: V
authors.lastname: Paquis-Flucklinger
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Arakawa
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Arnold
authors.initials: A
authors.lastname: Munnich
authors.forename: Agnès
authors.initials: A
authors.lastname: Rötig
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000502:physiology; D002478:Cells, Cultured; D004252:DNA Mutational Analysis; D004272:DNA, Mitochondrial / Q000235:genetics*; D005260:Female; D005347:Fibroblasts; D017353:Gene Deletion; D006720:Homozygote; D006801:Humans; D007231:Infant, Newborn; D008126:Lod Score; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008931:Mitochondria, Muscle; D028361:Mitochondrial Diseases / Q000209:etiology* / Q000473:pathology; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D012264:Ribonucleotide Reductases / Q000235:genetics* / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; D004272:DNA, Mitochondrial; D016159:Tumor Suppressor Protein p53; C405947:RRM2B protein, human; D012264:Ribonucleotide Reductases; C486561:Rrm2b protein, mouse