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.

Mitochondrial DNA Depletion and Deletions in Paediatric Patients with Neuromuscular Diseases: Novel Phenotypes

“…Patient 1 manifested with a severe progressive metabolic encephalomyopathy and the brain MRI of Patient 1 disclosed white matter degeneration as well as basal ganglia and thalamic lesions resembling Leigh syndrome. Similar encephalopathic phenotypes have been described in MDDS caused by several mtDNA maintenance genes including in SUCLA2 and SUCLG1 (Ostergaard et al 2007a, b;Carrozzo et al 2007;Elpeleg et al 2005), DGUOK (Mandel et al 2001;Dimmock et al 2008) and RRM2B (Bornstein et al 2008;Acham-Roschitz et al 2009;Kollberg et al 2009). Patient 1 was also found with generalized aminoaciduria that has previously been described in MDDS patients (Uusimaa et al 2014).…”

Mammalian ribonucleotide reductase subunit p53R2 is required for mitochondrial DNA replication and DNA repair in quiescent cells

“…They found that skeletal muscle of patients with mutations in the RRM2B gene coding for p53R2 completely lacked mtDNA (11). Similar patients were described in later studies from several other laboratories (12)(13)(14)(15)(16). It is now clear that p53R2 activity is required for the stability of the mt genome in differentiated tissues, shifting the attention from DNA repair to mtDNA maintenance.…”

Mitochondrial DNA Depletion Syndromes: Review and Updates of Genetic Basis, Manifestations, and Therapeutic Options

“…Affected individuals typically present during the first months of life with hypotonia, lactic acidosis, failure to thrive, tubulopathy, microcephaly, psychomotor delay, sensorineural hearing loss, and profound mtDNA depletion in muscle. The disease progresses rapidly, leading to death in few months [4,[31][32][33][34]. RRM2B mutations have also been reported to cause a mitochondrial neurogastrointestinal encephalopathy (MNGIE)-like phenotype with mtDNA depletion [35] and autosomal-dominant progressive external ophthalmoplegia (PEO) with multiple mtDNA deletions [36,37].…”