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Jacobson MD PhD Memorial Fund","award":["R01 EY029341"],"award-info":[{"award-number":["R01 EY029341"]}]},{"name":"the S.G. Jacobson MD PhD Memorial Fund","award":["P30 EY003039-43"],"award-info":[{"award-number":["P30 EY003039-43"]}]},{"name":"the S.G. Jacobson MD PhD Memorial Fund","award":["I K6 BX005787"],"award-info":[{"award-number":["I K6 BX005787"]}]},{"name":"unrestricted funds","award":["R01 EY029341"],"award-info":[{"award-number":["R01 EY029341"]}]},{"name":"unrestricted funds","award":["P30 EY003039-43"],"award-info":[{"award-number":["P30 EY003039-43"]}]},{"name":"unrestricted funds","award":["I K6 BX005787"],"award-info":[{"award-number":["I K6 BX005787"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Modern advances in disease genetics have uncovered numerous modifier genes that play a role in the severity of disease expression. One such class of genetic conditions is known as inherited retinal degenerations (IRDs), a collection of retinal degenerative disorders caused by mutations in over 300 genes. A single missense mutation (K42E) in the gene encoding the enzyme dehydrodolichyl diphosphate synthase (DHDDS), which is required for protein N-glycosylation in all cells and tissues, causes DHDDS-IRD (retinitis pigmentosa type 59 (RP59; OMIM #613861)). Apart from a retinal phenotype, however, DHDDS-IRD is surprisingly non-syndromic (i.e., without any systemic manifestations). To explore disease pathology, we selected five glycosylation-related genes for analysis that are suggested to have disease modifier variants. These genes encode glycosyltransferases (ALG6, ALG8), an ER resident protein (DDOST), a high-mannose oligosaccharyl transferase (MPDU1), and a protein N-glycosylation regulatory protein (TNKS). DNA samples from 11 confirmed DHDDS (K42E)-IRD patients were sequenced at the site of each candidate genetic modifier. Quantitative measures of retinal structure and function were performed across five decades of life by evaluating foveal photoreceptor thickness, visual acuity, foveal sensitivity, macular and extramacular rod sensitivity, and kinetic visual field extent. The ALG6 variant, (F304S), was correlated with greater macular cone disease severity and less peripheral rod disease severity. Thus, modifier gene polymorphisms may account for a significant portion of phenotypic variation observed in human genetic disease. However, the consequences of the polymorphisms may be counterintuitively complex in terms of rod and cone populations affected in different regions of the retina.<\/jats:p>","DOI":"10.3390\/ijms25021004","type":"journal-article","created":{"date-parts":[[2024,1,15]],"date-time":"2024-01-15T04:03:26Z","timestamp":1705291406000},"page":"1004","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Inherited Retinal Degeneration Caused by Dehydrodolichyl Diphosphate Synthase Mutation\u2013Effect of an ALG6 Modifier Variant"],"prefix":"10.3390","volume":"25","author":[{"given":"Elisha","family":"Monson","sequence":"first","affiliation":[{"name":"Department of Optometry and Vision Science, University of Alabama at Birmingham, Birmingham, AL 35294, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2018-0905","authenticated-orcid":false,"given":"Artur V.","family":"Cideciyan","sequence":"additional","affiliation":[{"name":"Center for Hereditary Retinal Degenerations, Scheie Eye Institute, Department of Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7368-3007","authenticated-orcid":false,"given":"Alejandro J.","family":"Roman","sequence":"additional","affiliation":[{"name":"Center for Hereditary Retinal Degenerations, Scheie Eye Institute, Department of Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Sumaroka","sequence":"additional","affiliation":[{"name":"Center for Hereditary Retinal Degenerations, Scheie Eye Institute, Department of Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Malgorzata","family":"Swider","sequence":"additional","affiliation":[{"name":"Center for Hereditary Retinal Degenerations, Scheie Eye Institute, Department of Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vivian","family":"Wu","sequence":"additional","affiliation":[{"name":"Center for Hereditary Retinal Degenerations, Scheie Eye Institute, Department of Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iryna","family":"Viarbitskaya","sequence":"additional","affiliation":[{"name":"Center for Hereditary Retinal Degenerations, Scheie Eye Institute, Department of Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel G.","family":"Jacobson","sequence":"additional","affiliation":[{"name":"Center for Hereditary Retinal Degenerations, Scheie Eye Institute, Department of Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2557-142X","authenticated-orcid":false,"given":"Steven J.","family":"Fliesler","sequence":"additional","affiliation":[{"name":"Departments of Ophthalmology and Biochemistry, and Neuroscience Graduate Program, Jacobs School of Medicine and Biomedical Sciences, State University of New York\u2014University at Buffalo, Buffalo, NY 14203, USA"},{"name":"Research Service, VA Western NY Healthcare System, Buffalo, NY 14215, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8464-9303","authenticated-orcid":false,"given":"Steven J.","family":"Pittler","sequence":"additional","affiliation":[{"name":"Department of Optometry and Vision Science, University of Alabama at Birmingham, Birmingham, AL 35294, USA"},{"name":"Vision Science Research Center, School of Optometry, University of Alabama at Birmingham, Birmingham, AL 35294, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,1,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1093\/glycob\/3.2.97","article-title":"Biological roles of oligosaccharides: All of the theories are correct","volume":"3","author":"Varki","year":"1993","journal-title":"Glycobiology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1002\/prca.200900161","article-title":"Glycoproteomics and clinical applications","volume":"4","author":"Tian","year":"2010","journal-title":"Proteom. 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