title: Mitochondrial DNA depletion syndrome due to mutations in the RRM2B gene.
abstract: Mitochondrial DNA depletion syndrome (MDS) is characterized by a reduction in mtDNA copy number and has been associated with mutations in eight nuclear genes, including enzymes involved in mitochondrial nucleotide metabolism (POLG, TK2, DGUOK, SUCLA2, SUCLG1, PEO1) and MPV17. Recently, mutations in the RRM2B gene, encoding the p53-controlled ribonucleotide reductase subunit, have been described in seven infants from four families, who presented with various combinations of hypotonia, tubulopathy, seizures, respiratory distress, diarrhea, and lactic acidosis. All children died before 4 months of age. We sequenced the RRM2B gene in three unrelated cases with unexplained severe mtDNA depletion. The first patient developed intractable diarrhea, profound weakness, respiratory distress, and died at 3 months. The other two unrelated patients had a much milder phenotype and are still alive at ages 27 and 36 months. All three patients had lactic acidosis and severe depletion of mtDNA in muscle. Muscle histochemistry showed RRF and COX deficiency. Sequencing the RRM2B gene revealed three missense mutations and two single nucleotide deletions in exons 6, 8, and 9, confirming that RRM2B mutations are important causes of MDS and that the clinical phenotype is heterogeneous and not invariably fatal in infancy.
authors.affiliation: Departamento de Bioquímica, Hospital Universitario Puerta de Hierro, Instituto de Investigaciones Biomédicas, CSIC-UAM, CIBERER, ISCiii, Madrid, Spain.
authors.forename: Belén
authors.initials: B
authors.lastname: Bornstein
authors.forename: Estela
authors.initials: E
authors.lastname: Area
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Flanigan
authors.forename: Jaya
authors.initials: J
authors.lastname: Ganesh
authors.forename: Parul
authors.initials: P
authors.lastname: Jayakar
authors.forename: Kathryn J
authors.initials: KJ
authors.lastname: Swoboda
authors.forename: Jorida
authors.initials: J
authors.lastname: Coku
authors.forename: Ali
authors.initials: A
authors.lastname: Naini
authors.forename: Sara
authors.initials: S
authors.lastname: Shanske
authors.forename: Kurenai
authors.initials: K
authors.lastname: Tanji
authors.forename: Michio
authors.initials: M
authors.lastname: Hirano
authors.forename: Salvatore
authors.initials: S
authors.lastname: DiMauro
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D004272:DNA, Mitochondrial / Q000235:genetics*; D005260:Female; D017353:Gene Deletion; D006801:Humans; D008297:Male; D028361:Mitochondrial Diseases / Q000209:etiology* / Q000235:genetics; D008958:Models, Molecular; D018482:Muscle, Skeletal / Q000473:pathology; D009154:Mutation; D012264:Ribonucleotide Reductases / Q000235:genetics*
chemical_list: D018797:Cell Cycle Proteins; D004272:DNA, Mitochondrial; C405947:RRM2B protein, human; D012264:Ribonucleotide Reductases