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Kearns–Sayre syndrome caused by defective R1/p53R2 assembly
  1. Robert D S Pitceathly1,
  2. Elisa Fassone2,3,
  3. Jan-Willem Taanman4,
  4. Michael Sadowski5,
  5. Carl Fratter6,
  6. Ese E Mudanohwo7,
  7. Cathy E Woodward7,
  8. Mary G Sweeney7,
  9. Janice L Holton1,8,
  10. Michael G Hanna1,8,
  11. Shamima Rahman1,2,9
  1. 1MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology and National Hospital for Neurology and Neurosurgery, London, UK
  2. 2Mitochondrial Research Group, Clinical and Molecular Genetics Unit, UCL Institute of Child Health, London, UK
  3. 3Dino Ferrari Centre, Department of Neurological Sciences, University of Milan, I.R.C.C.S. Foundation Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy
  4. 4Department of Clinical Neurosciences, UCL Institute of Neurology, London, UK
  5. 5Division of Mathematical Biology, National Institute for Medical Research, London, UK
  6. 6Oxford Regional Molecular Genetics Laboratory, Oxford Radcliffe Hospital NHS Trust, Oxford, UK
  7. 7Neurogenetics Unit, National Hospital for Neurology and Neurosurgery, Queen Square, London, UK
  8. 8Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK
  9. 9Metabolic Unit, Great Ormond Street Hospital for Children, London, UK
  1. Correspondence to Dr S Rahman, MRC Centre for Neuromuscular Diseases, National Hospital for Neurology and Neurosurgery, 8-11 Queen Square, London WC1N 3BG, UK; s.rahman{at}


Background Mutations in RRM2B encoding ribonucleotide reductase (RNR) p53R2 subunit usually cause paediatric-onset mitochondrial disease associated with mitochondrial DNA (mtDNA) depletion. The importance of RNR dysfunction in adult mitochondrial disease is unclear.

Objective To report the RRM2B mutation frequency in adults with multiple mtDNA deletions and examine RNR assembly in a patient with Kearns–Sayre syndrome (KSS) caused by two novel RRM2B mutations.

Methods 50 adult patients with multiple mtDNA deletions in skeletal muscle were studied. DNA sequencing of RRM2B was performed in patients without mutations in mtDNA maintenance genes POLG and C10orf2. RNR protein was studied using western blot and Blue-native polyacrylamide gel electrophoresis (BN-PAGE).

Results Four per cent (two unrelated cases) of this adult cohort harboured RRM2B mutations. Patient 1 had KSS and two novel missense mutations: c.122G→A; p.Arg41Gln and c.391G→A; p.Glu131Lys. BN-PAGE demonstrated reduced heterotetrameric R1/p53R2 RNR levels compared with controls, despite normal steady-state p53R2 levels on western blot, suggesting failed assembly of functional RNR as a potential disease mechanism. Patient 2 had late-onset progressive external ophthalmoplegia and fatigue. A heterozygous deletion c.253_255delGAG; p.Glu85del was identified. Muscle histology in both cases showed significant numbers of necrotic muscle fibres, possibly indicating enhanced apoptotic cell death.

Conclusion These data indicate that 4% of adult mitochondrial disease with multiple deletions is caused by RNR dysfunction. KSS has not previously been linked to a nuclear gene defect. Evidence that disease pathogenesis may be caused by defective RNR assembly is given. RRM2B screening should be considered early in the differential diagnosis of adults with multiple mtDNA deletions.

  • RRM2B
  • mitochondrial disease
  • Kearns-Sayre syndrome
  • clinical genetics
  • molecular genetics
  • neurology
  • neuromuscular disease

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  • Funding RDSP is funded by MRC grant number G0800674. MGH is supported by an MRC Centre grant G0601943; SR is supported by Great Ormond Street Hospital Children's Charity; JH and MGH are supported by the Myositis Support Group; and JH is supported by the Reta Lila Weston Institute for Neurological Studies. This study was supported by the NIHR UCLH/UCL Comprehensive Biomedical Research Centre and undertaken at University College London Hospitals/University College London, which received a proportion of funding from the Department of Health's National Institute for Health Research Biomedical Research Centres funding scheme.

  • Competing interests None.

  • Ethics approval This study was conducted with the approval of the Central London REC 3 09/H0716/76.

  • Provenance and peer review Not commissioned; externally peer reviewed.