RPE65 variant p.(E519K) causes a novel dominant adult-onset maculopathy in 83 affected individuals

RPE65 variant p.(E519K) causes a novel dominant adult-onset maculopathy in 83 affected individuals | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article RPE65 variant p.(E519K) causes a novel dominant adult-onset maculopathy in 83 affected individuals Eline Van Vooren, Filip Van den Broeck, Quinten Mahieu, Eline Geens, and 34 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5849564/v2 This work is licensed under a CC BY 4.0 License Status: Posted Version 2 posted You are reading this latest preprint version Show more versions Abstract Recessive RPE65-related retinopathy is an inherited retinal disease (IRD) that is a well-established target for gene therapy. Dominant RPE65-related retinopathy, however, due to Irish founder variant p.(D477G), is extremely rare. Here, we report the discovery, replication and characterization of a novel dominant retinopathy caused by RPE65 variant p.(E519K), identified in 83 individuals of European ancestry across IRD registries (Belgian discovery cohort, n=2,873; replication cohort, n=18,796). Long-read sequencing-based haplotyping revealed a shared region of 464 kb, supporting a founder effect. Genotype-phenotype data support dominant inheritance and phenotypic variability respectively, characterized by late-onset macular dystrophy with two main subtypes, a pathognomonic mottled subtype and a pattern dystrophy subtype. Functional studies showed that the p.(E519K) variant affects RPE65 enzymatic activity, correlating with lower protein expression. Protein modelling and cellular thermal shift assays further supported a destabilizing effect on protein structure. Overall, our work provides strong genetic, clinical, molecular and functional evidence for a novel dominant RPE65 retinopathy in multiple families in Europe and North America due to a Belgian founder variant. This discovery reduces the diagnostic gap in dominant IRD, particularly in individuals of European ancestry. Finally, it lays the foundation for developing therapeutic strategies targeting dominant RPE65 retinopathy. Molecular Genetics Medical Genetics Ophthalmology Autosomal dominant European ancestry Founder Inherited Retinal Disease (IRD) RPE65 Full Text Additional Declarations The authors declare no competing interests. Supplementary Files Supplementalfiguresandtables.pdf Supplemental figures and tables Cite Share Download PDF Status: Posted Version 2 posted You are reading this latest preprint version Show more versions Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5849564","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":444508086,"identity":"3705db76-e362-490b-80a1-dc906bcc02cc","order_by":0,"name":"Eline Van Vooren","email":"","orcid":"https://orcid.org/0000-0002-8731-1199","institution":"Department of Biomolecular Medicine, Ghent University, Ghent, Belgium","correspondingAuthor":false,"prefix":"","firstName":"Eline","middleName":"Van","lastName":"Vooren","suffix":""},{"id":444508087,"identity":"304a1df8-4636-4a40-baed-65a281dc9d7f","order_by":1,"name":"Filip Van den Broeck","email":"","orcid":"https://orcid.org/0009-0006-3330-6497","institution":"Department of Head and Skin, Ghent University, Ghent, Belgium; Department of Ophthalmology, Ghent University Hospital, Ghent, Belgium","correspondingAuthor":false,"prefix":"","firstName":"Filip","middleName":"Van den","lastName":"Broeck","suffix":""},{"id":444508088,"identity":"529b25a1-de65-4efb-9b8f-e0ac3f863fa7","order_by":2,"name":"Quinten Mahieu","email":"","orcid":"https://orcid.org/0000-0002-0850-1745","institution":"Department of Biomolecular Medicine, Ghent University, Ghent, Belgium","correspondingAuthor":false,"prefix":"","firstName":"Quinten","middleName":"","lastName":"Mahieu","suffix":""},{"id":444508089,"identity":"81f57dd0-029d-41ca-9d38-644236624ef2","order_by":3,"name":"Eline Geens","email":"","orcid":"","institution":"Department of Biomolecular Medicine, Ghent University, Ghent, Belgium","correspondingAuthor":false,"prefix":"","firstName":"Eline","middleName":"","lastName":"Geens","suffix":""},{"id":444508090,"identity":"1319b48a-0fef-4019-af7f-4db5f97d3fdb","order_by":4,"name":"Mattias Van Heetvelde","email":"","orcid":"","institution":"Department of Biomolecular Medicine, Ghent University, Ghent, Belgium","correspondingAuthor":false,"prefix":"","firstName":"Mattias","middleName":"Van","lastName":"Heetvelde","suffix":""},{"id":444508091,"identity":"af37d342-2081-4916-bb1f-63d188cc33a3","order_by":5,"name":"Marieke De Bruyne","email":"","orcid":"https://orcid.org/0000-0001-6636-5537","institution":"Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium","correspondingAuthor":false,"prefix":"","firstName":"Marieke","middleName":"","lastName":"De Bruyne","suffix":""},{"id":444508092,"identity":"e53e3cba-3540-4e55-b765-fa325f2f9408","order_by":6,"name":"Stijn Van de Sompele","email":"","orcid":"https://orcid.org/0000-0002-3294-0668","institution":"Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium","correspondingAuthor":false,"prefix":"","firstName":"Stijn","middleName":"Van","lastName":"de Sompele","suffix":""},{"id":444508093,"identity":"3a0defce-8f95-45c0-a08e-b78778062069","order_by":7,"name":"Sheetal Uppal","email":"","orcid":"https://orcid.org/0000-0002-3685-8602","institution":"Laboratory of Retinal Cell and Molecular Biology, National Eye Institute, NIH, Bethesda, United States","correspondingAuthor":false,"prefix":"","firstName":"Sheetal","middleName":"","lastName":"Uppal","suffix":""},{"id":444508094,"identity":"cfe2c2a0-dc6f-4441-bd4d-d89ed821b870","order_by":8,"name":"Eugenia Poliakov","email":"","orcid":"","institution":"Laboratory of Retinal Cell and Molecular Biology, National Eye Institute, NIH, Bethesda, United States","correspondingAuthor":false,"prefix":"","firstName":"Eugenia","middleName":"","lastName":"Poliakov","suffix":""},{"id":444508095,"identity":"7626393a-6608-47f6-8d12-f4ccae658c2e","order_by":9,"name":"Claire-Marie Dhaenens","email":"","orcid":"https://orcid.org/0000-0003-4719-4124","institution":"Univ. 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1803816N; 1SE7223N","order_by":2}],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"Ghent University","isAcceptedByJournal":false,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Autosomal dominant; European ancestry; Founder; Inherited Retinal Disease (IRD); RPE65","lastPublishedDoi":"10.21203/rs.3.rs-5849564/v2","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5849564/v2","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eRecessive RPE65-related retinopathy is an inherited retinal disease (IRD) that is a well-established target for gene therapy. Dominant RPE65-related retinopathy, however, due to Irish founder variant p.(D477G), is extremely rare. Here, we report the discovery, replication and characterization of a novel dominant retinopathy caused by RPE65 variant p.(E519K), identified in 83 individuals of European ancestry across IRD registries (Belgian discovery cohort, n=2,873; replication cohort, n=18,796). Long-read sequencing-based haplotyping revealed a shared region of 464 kb, supporting a founder effect. Genotype-phenotype data support dominant inheritance and phenotypic variability respectively, characterized by late-onset macular dystrophy with two main subtypes, a pathognomonic mottled subtype and a pattern dystrophy subtype.\u003cstrong\u003e \u003c/strong\u003eFunctional studies showed that the p.(E519K) variant affects RPE65 enzymatic activity, correlating with lower protein expression. Protein modelling and cellular thermal shift assays further supported a destabilizing effect on protein structure. Overall, our work provides strong genetic, clinical, molecular and functional evidence for a novel dominant RPE65 retinopathy in multiple families in Europe and North America due to a Belgian founder variant. This discovery reduces the diagnostic gap in dominant IRD, particularly in individuals of European ancestry. Finally, it lays the foundation for developing therapeutic strategies targeting dominant RPE65 retinopathy.\u003c/p\u003e","manuscriptTitle":"RPE65 variant p.(E519K) causes a novel dominant adult-onset maculopathy in 83 affected individuals","msid":"","msnumber":"","nonDraftVersions":[{"code":2,"date":"2025-05-05 18:25:20","doi":"10.21203/rs.3.rs-5849564/v2","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}},{"code":1,"date":"2025-02-05 05:58:52","doi":"10.21203/rs.3.rs-5849564/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"d38a9229-cfa6-4221-84ea-6e6220b019e9","owner":[],"postedDate":"May 5th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":47354206,"name":"Molecular Genetics"},{"id":47354207,"name":"Medical Genetics"},{"id":47354208,"name":"Ophthalmology"}],"tags":[],"updatedAt":"2025-02-05T05:58:53+00:00","versionOfRecord":[],"versionCreatedAt":"2025-05-05 18:25:20","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v2","identity":"rs-5849564","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5849564","identity":"rs-5849564","version":["v2"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}