{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,12]],"date-time":"2026-03-12T04:58:08Z","timestamp":1773291488449,"version":"3.50.1"},"reference-count":26,"publisher":"BMJ","issue":"9","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J Med Genet"],"accepted":{"date-parts":[[2011,1,13]]},"published-print":{"date-parts":[[2011,9]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Mutations in\n                      <jats:italic>RRM2B<\/jats:italic>\n                      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.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>\n                      To report the\n                      <jats:italic>RRM2B<\/jats:italic>\n                      mutation frequency in adults with multiple mtDNA deletions and examine RNR assembly in a patient with Kearns\u2013Sayre syndrome (KSS) caused by two novel\n                      <jats:italic>RRM2B<\/jats:italic>\n                      mutations.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      50 adult patients with multiple mtDNA deletions in skeletal muscle were studied. DNA sequencing of\n                      <jats:italic>RRM2B<\/jats:italic>\n                      was performed in patients without mutations in mtDNA maintenance genes\n                      <jats:italic>POLG<\/jats:italic>\n                      and\n                      <jats:italic>C10orf2<\/jats:italic>\n                      . RNR protein was studied using western blot and Blue-native polyacrylamide gel electrophoresis (BN-PAGE).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Four per cent (two unrelated cases) of this adult cohort harboured\n                      <jats:italic>RRM2B<\/jats:italic>\n                      mutations. Patient 1 had KSS and two novel missense mutations: c.122G\u2192A; p.Arg41Gln and c.391G\u2192A; 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.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      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.\n                      <jats:italic>RRM2B<\/jats:italic>\n                      screening should be considered early in the differential diagnosis of adults with multiple mtDNA deletions.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jmg.2010.088328","type":"journal-article","created":{"date-parts":[[2011,3,5]],"date-time":"2011-03-05T20:14:05Z","timestamp":1299356045000},"page":"610-617","source":"Crossref","is-referenced-by-count":49,"title":["Kearns\u2013Sayre syndrome caused by defective R1\/p53R2 assembly"],"prefix":"10.1136","volume":"48","author":[{"given":"Robert D S","family":"Pitceathly","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elisa","family":"Fassone","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jan-Willem","family":"Taanman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Sadowski","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carl","family":"Fratter","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ese E","family":"Mudanohwo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cathy E","family":"Woodward","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mary G","family":"Sweeney","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Janice L","family":"Holton","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael G","family":"Hanna","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shamima","family":"Rahman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"239","published-online":{"date-parts":[[2011,3,4]]},"reference":[{"key":"2025101710463950000_48.9.610.1","doi-asserted-by":"publisher","DOI":"10.1038\/ng2040"},{"key":"2025101710463950000_48.9.610.2","doi-asserted-by":"publisher","DOI":"10.1016\/j.nmd.2008.04.006"},{"key":"2025101710463950000_48.9.610.3","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2009.06.012"},{"key":"2025101710463950000_48.9.610.4","doi-asserted-by":"publisher","DOI":"10.1016\/j.nmd.2008.11.014"},{"key":"2025101710463950000_48.9.610.5","doi-asserted-by":"publisher","DOI":"10.1136\/adc.2008.147983"},{"key":"2025101710463950000_48.9.610.6","doi-asserted-by":"publisher","DOI":"10.1001\/archneurol.2009.139"},{"key":"2025101710463950000_48.9.610.7","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2009.07.009"},{"key":"2025101710463950000_48.9.610.8","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1038\/35003506","article-title":"A ribonucleotide reductase gene involved in a p53-dependent cell-cycle checkpoint for DNA damage","volume":"404","author":"Tanaka","year":"2000","journal-title":"Nature"},{"key":"2025101710463950000_48.9.610.9","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1203774"},{"key":"2025101710463950000_48.9.610.10","first-page":"8256","article-title":"p53R2-dependent pathway for DNA synthesis in a p53-regulated cell cycle checkpoint","volume":"61","author":"Yamaguchi","year":"2001","journal-title":"Cancer Res"},{"key":"2025101710463950000_48.9.610.11","unstructured":"Shoffner J Shoubridge E . 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