Mutation of RRM2B, encoding p53-controlled ribonucleotide reductase (p53R2), causes severe mitochondrial DNA depletion.
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.
Bourdon
Alice
A
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.
Minai
Limor
L
Serre
Valérie
V
Jais
Jean-Philippe
JP
Sarzi
Emmanuelle
E
Aubert
Sophie
S
Chrétien
Dominique
D
de Lonlay
Pascale
P
Paquis-Flucklinger
Véronique
V
Arakawa
Hirofumi
H
Nakamura
Yusuke
Y
Munnich
Arnold
A
Rötig
Agnès
A
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*
D018797:Cell Cycle Proteins; D004272:DNA, Mitochondrial; D016159:Tumor Suppressor Protein p53; C405947:RRM2B protein, human; D012264:Ribonucleotide Reductases; C486561:Rrm2b protein, mouse