{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T09:24:06Z","timestamp":1791365046102,"version":"4.3.1"},"reference-count":56,"publisher":"National Academy of Sciences","issue":"49","license":[{"start":{"date-parts":[[2022,11,29]],"date-time":"2022-11-29T00:00:00Z","timestamp":1669680000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2022,12,6]]},"abstract":"<jats:p>\n                    Pathogenic variants in the\n                    <jats:italic>Retinitis pigmentosa GTPase regulator (RPGR)<\/jats:italic>\n                    gene lead to a clinically severe form of X-linked retinal dystrophy. However, it remains unclear why some variants cause a predominant rod, while others result in a cone-dominated phenotype. Post-translational glutamylation of the photoreceptor-specific RPGR\n                    <jats:sup>ORF15<\/jats:sup>\n                    isoform by the TTLL5 enzyme is essential for its optimal function in photoreceptors, and loss of TTLL5 leads to retinal dystrophy with a cone phenotype. Here we show that RPGR retinal disease, studied in a single cohort of 116 male patients, leads to a clear progressive shift from rod- to cone-dominating phenotype as the RPGR\n                    <jats:sup>ORF15<\/jats:sup>\n                    variant location approaches the distal part of the Open Reading Frame 15 (ORF15) region. The rod photoreceptor involvement on the contrary diminishes along the RGPR sequence, and the variants associated with the cone only phenotype are located predominantly in the very distal part, including the C-terminal basic domain. Moreover, these distal truncating RPGR\n                    <jats:sup>ORF15<\/jats:sup>\n                    variants disrupt the interaction with TTLL5 and lead to a significant impairment of RPGR glutamylation. Thus, consistent with the phenotype of TTLL5 pathogenic variants, our study shows that RPGR\n                    <jats:sup>ORF15<\/jats:sup>\n                    variants, which disrupt its basic domain and the interaction with TTLL5, also impair RPGR glutamylation and lead to the cone phenotype. This has implications for ongoing gene therapy clinical trials where the application of RPGR with impaired glutamylation may be less effective in treating RGPR dystrophies and may even convert a rod\u2013cone dystrophy into a cone dystrophy phenotype.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2208707119","type":"journal-article","created":{"date-parts":[[2022,11,29]],"date-time":"2022-11-29T14:26:57Z","timestamp":1669732017000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":44,"title":["Impaired glutamylation of RPGR\n                    <sup>ORF15<\/sup>\n                    underlies the cone-dominated phenotype associated with truncating distal ORF15 variants"],"prefix":"10.1073","volume":"119","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9956-6412","authenticated-orcid":false,"given":"Jasmina","family":"Cehajic-Kapetanovic","sequence":"first","affiliation":[{"name":"Nuffield Laboratory of Ophthalmology, Department of Clinical Neurosciences, John Radcliffe Hospital, Level 5 &amp; 6, West Wing OX3 9DU, United Kingdom"},{"name":"Oxford Eye Hospital, Oxford University Hospitals The National Health Service Trust, John Radcliffe Hospital, West Wing OX3 9DU, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6612-6162","authenticated-orcid":false,"given":"Cristina","family":"Martinez-Fernandez de la Camara","sequence":"additional","affiliation":[{"name":"Nuffield Laboratory of Ophthalmology, Department of Clinical Neurosciences, John Radcliffe Hospital, Level 5 &amp; 6, West Wing OX3 9DU, United Kingdom"},{"name":"Oxford Eye Hospital, Oxford University Hospitals The National Health Service Trust, John Radcliffe Hospital, West Wing OX3 9DU, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7699-2112","authenticated-orcid":false,"given":"Johannes","family":"Birtel","sequence":"additional","affiliation":[{"name":"Nuffield Laboratory of Ophthalmology, Department of Clinical Neurosciences, John Radcliffe Hospital, Level 5 &amp; 6, West Wing OX3 9DU, United Kingdom"},{"name":"Oxford Eye Hospital, Oxford University Hospitals The National Health Service Trust, John Radcliffe Hospital, West Wing OX3 9DU, United Kingdom"},{"name":"Department of Ophthalmology, University of Bonn, 53127 Bonn, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salwah","family":"Rehman","sequence":"additional","affiliation":[{"name":"Nuffield Laboratory of Ophthalmology, Department of Clinical Neurosciences, John Radcliffe Hospital, Level 5 &amp; 6, West Wing OX3 9DU, United Kingdom"},{"name":"Oxford Eye Hospital, Oxford University Hospitals The National Health Service Trust, John Radcliffe Hospital, West Wing OX3 9DU, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2941-4464","authenticated-orcid":false,"given":"Michelle E.","family":"McClements","sequence":"additional","affiliation":[{"name":"Nuffield Laboratory of Ophthalmology, Department of Clinical Neurosciences, John Radcliffe Hospital, Level 5 &amp; 6, West Wing OX3 9DU, United Kingdom"},{"name":"Oxford Eye Hospital, Oxford University Hospitals The National Health Service Trust, John Radcliffe Hospital, West Wing OX3 9DU, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0351-6673","authenticated-orcid":false,"given":"Peter","family":"Charbel Issa","sequence":"additional","affiliation":[{"name":"Nuffield Laboratory of Ophthalmology, Department of Clinical Neurosciences, John Radcliffe Hospital, Level 5 &amp; 6, West Wing OX3 9DU, United Kingdom"},{"name":"Oxford Eye Hospital, Oxford University Hospitals The National Health Service Trust, John Radcliffe Hospital, West Wing OX3 9DU, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5541-4305","authenticated-orcid":false,"given":"Andrew J","family":"Lotery","sequence":"additional","affiliation":[{"name":"Clinical Neurosciences Research Group, Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, SO16 6YD Southampton, United Kingdom"},{"name":"University Hospital Southampton NHS Foundation Trust, SO16 6YD Southampton, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert E.","family":"MacLaren","sequence":"additional","affiliation":[{"name":"Nuffield Laboratory of Ophthalmology, Department of Clinical Neurosciences, John Radcliffe Hospital, Level 5 &amp; 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