{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T06:03:30Z","timestamp":1791871410714,"version":"4.3.4"},"reference-count":26,"publisher":"The Company of Biologists","license":[{"start":{"date-parts":[[2021,5,18]],"date-time":"2021-05-18T00:00:00Z","timestamp":1621296000000},"content-version":"am","delay-in-days":1233,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100004440","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["100981\/Z\/13\/"],"award-info":[{"award-number":["100981\/Z\/13\/"]}],"id":[{"id":"10.13039\/100004440","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:p>Isocitrate dehydrogenase (IDH) is an enzyme required for the production of \u03b1-ketoglutarate from isocitrate. IDH3 generates the NADH used in the mitochondria for ATP production, and is a tetramer made up of two \u03b1, a \u03b2 and a \u03b3 subunit. Loss of function and missense mutations in both IDH3A andIDH3B have previously been implicated in families exhibiting retinal degeneration. Using mouse models we have investigated the role of IDH3 in retinal disease and mitochondrial function.<\/jats:p>\n               <jats:p>We identified mice with late-onset retinal degeneration in a screen of ageing mice carrying an ENU-induced mutation, E229K, in Idh3a. Mice homozygous for this mutation exhibit signs of retinal stress, indicated by GFAP staining, as early as 3 months, but no other tissues appear to be affected. We produced a knockout of Idh3a and found that homozygous mice do not survive past early embryogenesis. Idh3a\u2212\/E229K compound heterozygous mutants exhibit a more severe retinal degeneration when compared to Idh3aE229K\/E229K. Analysis of mitochondrial function in mutant cell lines highlighted a reduction in mitochondrial maximal respiration and reserve capacity levels in both Idh3aE229K\/E229K and Idh3a\u2212\/E229K cells. Loss-of function Idh3b mutants do not exhibit the same retinal degeneration phenotype, with no signs of retinal stress or reduction in mitochondrial respiration.<\/jats:p>\n               <jats:p>It has been previously reported that the retina operates with a limited mitochondrial reserve capacity and we suggest that this, in combination with the reduced reserve capacity in mutants, explains the degenerative phenotype observed in Idh3a mutant mice.<\/jats:p>","DOI":"10.1242\/dmm.036426","type":"journal-article","created":{"date-parts":[[2018,11,27]],"date-time":"2018-11-27T10:34:12Z","timestamp":1543314852000},"source":"Crossref","is-referenced-by-count":22,"title":["Mouse Idh3a mutations cause retinal degeneration and reduced mitochondrial function"],"prefix":"10.1242","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9382-5911","authenticated-orcid":false,"given":"Amy S.","family":"Findlay","sequence":"first","affiliation":[{"name":"MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road, Edinburgh EH4 2XU, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roderick N.","family":"Carter","sequence":"additional","affiliation":[{"name":"Molecular Metabolism Group, Centre for Cardiovascular Sciences, Queens Medical Research Institute, University of Edinburgh, EH16 4TJ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Becky","family":"Starbuck","sequence":"additional","affiliation":[{"name":"MRC Mammalian Genetics Unit, MRC Harwell Institute, Harwell Campus, Oxfordshire, OX11 0RD, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa","family":"McKie","sequence":"additional","affiliation":[{"name":"MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road, Edinburgh EH4 2XU, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kl\u00e1ra","family":"Nov\u00e1kov\u00e1","sequence":"additional","affiliation":[{"name":"MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road, Edinburgh EH4 2XU, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8951-2413","authenticated-orcid":false,"given":"Peter S.","family":"Budd","sequence":"additional","affiliation":[{"name":"MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road, Edinburgh EH4 2XU, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margaret A.","family":"Keighren","sequence":"additional","affiliation":[{"name":"MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road, Edinburgh EH4 2XU, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph A.","family":"Marsh","sequence":"additional","affiliation":[{"name":"MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road, Edinburgh EH4 2XU, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sally H.","family":"Cross","sequence":"additional","affiliation":[{"name":"MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road, Edinburgh EH4 2XU, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle M.","family":"Simon","sequence":"additional","affiliation":[{"name":"MRC Mammalian Genetics Unit, MRC Harwell Institute, Harwell Campus, Oxfordshire, OX11 0RD, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul K.","family":"Potter","sequence":"additional","affiliation":[{"name":"MRC Mammalian Genetics Unit, MRC Harwell Institute, Harwell Campus, Oxfordshire, OX11 0RD, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas M.","family":"Morton","sequence":"additional","affiliation":[{"name":"Molecular Metabolism Group, Centre for Cardiovascular Sciences, Queens Medical Research Institute, University of Edinburgh, EH16 4TJ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6526-0688","authenticated-orcid":false,"given":"Ian J.","family":"Jackson","sequence":"additional","affiliation":[{"name":"MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road, Edinburgh EH4 2XU, UK"},{"name":"Roslin Institute, University of Edinburgh, Edinburgh EH25 9RG, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","published-online":{"date-parts":[[2018,1,1]]},"reference":[{"key":"2021042500480728100_DMM036426C26","doi-asserted-by":"publisher","first-page":"151","DOI":"10.1016\/j.ajhg.2016.11.014","article-title":"Mutations in MDH2, encoding a Krebs cycle enzyme, cause early-onset severe encephalopathy","volume":"100","author":"Ait-El-Mkadem","year":"2017","journal-title":"Am. 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