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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. )) or the salvage pathway of mitochondrial deoxyribonucleosides 5′-triphosphates (dNTPs) for mtDNA synthesis (DGUOK (ref. ), TK2 (ref. ) and SUCLA2 (ref. )). A last gene, MPV17 (ref. ), 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 …