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Although dominantly inherited, pathogenic variants in\n                    <jats:italic>POLG<\/jats:italic>\n                    ,\n                    <jats:italic>TWNK<\/jats:italic>\n                    and\n                    <jats:italic>RRM2B<\/jats:italic>\n                    are among the most common genetic defects of adPEO, identification of novel candidate genes and the underlying pathomechanisms remains challenging. We report the clinical, genetic and molecular investigations of a patient who presented in the seventh decade of life with PEO. Oxidative histochemistry revealed cytochrome\n                    <jats:italic>c<\/jats:italic>\n                    oxidase\u2010deficient fibres and occasional ragged red fibres showing subsarcolemmal mitochondrial accumulation in skeletal muscle, while molecular studies identified the presence of multiple mtDNA deletions. Negative candidate screening of known nuclear genes associated with PEO prompted diagnostic exome sequencing, leading to the prioritisation of a novel heterozygous c.547G&gt;C variant in\n                    <jats:italic>GMPR<\/jats:italic>\n                    (NM_006877.3) encoding guanosine monophosphate reductase, a cytosolic enzyme required for maintaining the cellular balance of adenine and guanine nucleotides. We show that the novel c.547G&gt;C variant causes aberrant splicing, decreased GMPR protein levels in patient skeletal muscle, proliferating and quiescent cells, and is associated with subtle changes in nucleotide homeostasis protein levels and evidence of disturbed mtDNA maintenance in skeletal muscle. Despite confirmation of GMPR deficiency, demonstrating marked defects of mtDNA replication or nucleotide homeostasis in patient cells proved challenging. Our study proposes that\n                    <jats:italic>GMPR<\/jats:italic>\n                    is the 19th locus for PEO and highlights the complexities of uncovering disease mechanisms in late\u2010onset PEO phenotypes.\n                  <\/jats:p>","DOI":"10.1111\/cge.13652","type":"journal-article","created":{"date-parts":[[2019,10,10]],"date-time":"2019-10-10T19:36:41Z","timestamp":1570736201000},"page":"276-286","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Identification of a novel heterozygous guanosine monophosphate reductase (\n                    <i>GMPR<\/i>\n                    ) variant in a patient with a late\u2010onset disorder of mitochondrial DNA maintenance"],"prefix":"10.1111","volume":"97","author":[{"given":"Ewen W.","family":"Sommerville","sequence":"first","affiliation":[{"name":"Wellcome Centre for Mitochondrial Research, Institute of Neuroscience Newcastle University  Newcastle 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Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kyle","family":"Thompson","sequence":"additional","affiliation":[{"name":"Wellcome Centre for Mitochondrial Research, Institute of Neuroscience Newcastle University  Newcastle upon Tyne UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mariana","family":"Rocha","sequence":"additional","affiliation":[{"name":"Wellcome Centre for Mitochondrial Research, Institute of Neuroscience Newcastle University  Newcastle upon Tyne UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emma L.","family":"Blakely","sequence":"additional","affiliation":[{"name":"Wellcome Centre for Mitochondrial Research, Institute of Neuroscience Newcastle University  Newcastle upon Tyne UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Langping","family":"He","sequence":"additional","affiliation":[{"name":"Wellcome Centre for Mitochondrial Research, Institute of Neuroscience Newcastle University  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UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Patrick F.","family":"Chinnery","sequence":"additional","affiliation":[{"name":"Department of Clinical Neuroscience &amp; Medical Research Council Mitochondrial Biology Unit School of Clinical Medicine, University of Cambridge  Cambridge UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lizbeth","family":"Hedstrom","sequence":"additional","affiliation":[{"name":"Department of Biology Brandeis University  Waltham MA"},{"name":"Department of Chemistry Brandeis University, 415 South St.  Waltham MA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Antonella","family":"Spinazzola","sequence":"additional","affiliation":[{"name":"Department of Clinical and Movement Neurosciences, UCL Queens Square Institute of Neurology, Royal Free Campus University College London  London UK"},{"name":"MRC Centre for Neuromuscular Diseases UCL Institute of Neurology and National Hospital for Neurology and Neurosurgery  London UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7768-8873","authenticated-orcid":false,"given":"Robert W.","family":"Taylor","sequence":"additional","affiliation":[{"name":"Wellcome Centre for Mitochondrial Research, Institute of Neuroscience Newcastle University  Newcastle upon Tyne UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gr\u00e1inne S.","family":"Gorman","sequence":"additional","affiliation":[{"name":"Wellcome Centre for Mitochondrial Research, Institute of Neuroscience Newcastle University  Newcastle upon Tyne 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