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Published on: August 4, 2019
Kearns-Sayre syndrome caused by defective R1/p53R2 assembly
Robert D S Pitceathly1, Elisa Fassone, Jan-Willem Taanman
11MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology and National Hospital for Neurology and Neurosurgery, London, UK.
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.
Insights
Mutations in RRM2B cause adult mitochondrial disease with multiple mtDNA deletions in 4% of cases. This suggests defective ribonucleotide reductase (RNR) assembly may be a key disease mechanism.
Area of Science:
- Genetics
- Molecular Biology
- Neurology
Background:
- Mutations in RRM2B, encoding the p53R2 subunit of ribonucleotide reductase (RNR), are typically linked to childhood mitochondrial diseases and mitochondrial DNA (mtDNA) depletion.
- The role of RNR dysfunction in adult-onset mitochondrial disorders, particularly those involving multiple mtDNA deletions, remains largely undefined.
Purpose of the Study:
- To determine the frequency of RRM2B mutations in adults presenting with multiple mtDNA deletions.
- To investigate the impact of RRM2B mutations on RNR assembly in a patient with Kearns-Sayre syndrome (KSS).
Main Methods:
- DNA sequencing of the RRM2B gene was performed on 50 adult patients with skeletal muscle multiple mtDNA deletions, excluding those with mutations in POLG or C10orf2.
- Ribonucleotide reductase (RNR) protein levels and assembly were analyzed using western blotting and Blue-native polyacrylamide gel electrophoresis (BN-PAGE).
Main Results:
- RRM2B mutations were identified in 4% of the adult cohort (two unrelated patients).
- One patient with KSS had two novel RRM2B mutations, and BN-PAGE revealed reduced levels of the functional heterotetrameric R1/p53R2 RNR complex, indicating impaired RNR assembly.
- The second patient presented with late-onset progressive external ophthalmoplegia and fatigue, associated with a heterozygous deletion in RRM2B. Both patients exhibited muscle fiber necrosis.
Conclusions:
- RNR dysfunction due to RRM2B mutations accounts for 4% of adult mitochondrial diseases characterized by multiple mtDNA deletions.
- This study provides the first evidence linking KSS to a nuclear gene defect (RRM2B) and suggests defective RNR assembly as a pathogenic mechanism.
- Early screening for RRM2B mutations is recommended for adults diagnosed with multiple mtDNA deletions.
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