{"doi":"10.1167/iovs.66.12.53","title":"RPE65 Variant p.(E519K) Causes a Novel Dominant Adult-Onset Maculopathy in 83 Affected Individuals","abstract":"Purpose: Recessive RPE65-associated retinopathy is a well-known target for gene therapy, whereas dominant RPE65-associated retinopathy, due to the Irish founder variant p.(D477G), has been reported only once until now and is very rare. Here, we present the discovery of a novel, second dominant RPE65-associated retinopathy caused by variant c.1555G>A, p.(E519K). Methods: Genomic data was investigated in a Belgian discovery cohort (n = 2873) and an international replication cohort (n = 18,796) with inherited retinal disease (IRD). Heterozygous p.(E519K) individuals underwent extensive phenotyping. Haplotype phasing was based on long-read sequencing and microsatellite analysis. Variant p.(E519K) was assessed in vitro using an enzymatic assay, Western blotting, co-immunoprecipitation, cellular thermal shift assay (CETSA), minigene assays, and in silico using protein modeling (AlphaFold). Results: The monoallelic p.(E519K) variant was found in 83 affected individuals from Belgium, the Netherlands, France, and Canada, all of European ancestry. A shared region of 464 kilobases (kb) confirmed a founder effect. Variant p.(E519K) lowers RPE65 protein expression and enzymatic activity, with altered protein stability predicted and experimentally confirmed. Genotype-phenotype data support dominant inheritance and phenotypic variability, respectively, characterized by late-onset macular dystrophy with two main subtypes. Conclusions: The discovery of a dominant RPE65-IRD due to founder variant p.(E519K) reduces the diagnostic gap in dominant IRD and highlights a novel target for therapy.","journal":"Investigative Ophthalmology & Visual Science","year":2025,"id":542354,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.888,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1278243,"name":"Filip Van den Broeck","orcid":"0009-0006-3330-6497","position":1,"is_corresponding":false},{"id":57032,"name":"Quinten Mahieu","orcid":"0000-0002-0850-1745","position":2,"is_corresponding":false},{"id":1431931,"name":"Eline Geens","orcid":null,"position":3,"is_corresponding":false},{"id":57093,"name":"Mattias Van Heetvelde","orcid":"0000-0001-5758-0366","position":4,"is_corresponding":false},{"id":56983,"name":"Marieke De Bruyne","orcid":"0000-0001-6636-5537","position":5,"is_corresponding":false},{"id":1246021,"name":"Stijn Van de Sompele","orcid":"0000-0002-3294-0668","position":6,"is_corresponding":false},{"id":392743,"name":"Sheetal Uppal","orcid":"0000-0002-3685-8602","position":7,"is_corresponding":false},{"id":392742,"name":"Eugenia Poliakov","orcid":"0000-0003-3865-8054","position":8,"is_corresponding":false},{"id":710592,"name":"Claire‐Marie Dhaenens","orcid":"0000-0003-4719-4124","position":9,"is_corresponding":false},{"id":1431432,"name":"Cheryl Y. Gregory‐Evans","orcid":"0000-0001-8613-0460","position":10,"is_corresponding":false},{"id":57008,"name":"Lies H. Hoefsloot","orcid":"0009-0000-3444-9955","position":11,"is_corresponding":false},{"id":80976,"name":"Adriana I. 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Thiadens","orcid":"0000-0002-4911-9462","position":26,"is_corresponding":false},{"id":1431434,"name":"Kirk Stephenson","orcid":"0000-0002-7462-7725","position":27,"is_corresponding":false},{"id":1425488,"name":"Narin Sheri","orcid":null,"position":28,"is_corresponding":false},{"id":854941,"name":"Vasily Smirnov","orcid":"0000-0003-4172-514X","position":29,"is_corresponding":false},{"id":368840,"name":"Ian M. MacDonald","orcid":"0000-0001-7472-8385","position":30,"is_corresponding":false},{"id":1431435,"name":"Kevin Gregory‐Evans","orcid":"0000-0003-3572-3105","position":31,"is_corresponding":false},{"id":392745,"name":"T. Michael Redmond","orcid":"0000-0002-1813-5291","position":32,"is_corresponding":false},{"id":56986,"name":"Julie De Zaeytijd","orcid":"0000-0003-4035-6389","position":33,"is_corresponding":false},{"id":57028,"name":"Bart P. 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