ArticleHuman molecular genetics2018
Insights into the pathogenesis of dominant retinitis pigmentosa associated with a D477G mutation in RPE65.
Article in Human molecular genetics, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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Who cites it
30 citing papers in PubMed, 37 citations in OpenAlex.
- Carrier screening in the reproductive setting-Are there medical implications for the heterozygote?-A guide for clinicians.Pregnancy (Hoboken, N.J.) · 2026Review
- Pathogenicity and Functional Analysis of Multi-Variant Allele of RPE65 Causing Retinitis Pigmentosa.Translational vision science & technology · 2026Article
- Dynamic Inner Blood Retina Barrier Disruption in Retinitis Pigmentosa.Investigative ophthalmology & visual science · 2025Article
- Higher Throughput Assays for Understanding the Pathogenicity of Variants of Unknown Significance in the RPE65 Gene.Investigative ophthalmology & visual science · 2025Article
- RPE65 Variant p.(E519K) Causes a Novel Dominant Adult-Onset Maculopathy in 83 Affected Individuals.Investigative ophthalmology & visual science · 2025Article
- Retinoid dynamics in vision: from visual cycle biology to retina disease treatments.Pharmacology & therapeutics · 2025Review
- Higher throughput assays for understanding the pathogenicity of variants of unknown significance (VUS) in the RPE65 gene.bioRxiv : the preprint server for biology · 2025Article
- Pathological Involvement of Protein Phase Separation and Aggregation in Neurodegenerative Diseases.International journal of molecular sciences · 2024Review
- Research Progress on the Role of Ubiquitination in Eye Diseases.Cell biochemistry and biophysics · 2024Review
- Gene Supplementation in Mice Heterozygous for the D477G RPE65 Variant Implicated in Autosomal Dominant Retinitis Pigmentosa.Human gene therapy · 2023Article
- The First Homozygote Mutation c.499G>T (Asp167Tyr) in the RPE65 Gene Encoding Retinoid Isomerohydrolase Causing Retinal DystrophyCurrent issues in molecular biology · 2022Article
- Retinoid therapy restores eye-specific cortical responses in adult mice with retinal degeneration.Current biology : CB · 2022Article
- Retinal pigment epithelium 65 kDa protein (RPE65): An update.Progress in retinal and eye research · 2022Review
- A large animal model of RDH5-associated retinopathy recapitulates important features of the human phenotype.Human molecular genetics · 2022Article
- The interplay of environmental luminance and genetics in the retinal dystrophy induced by the dominant RPE65 mutation.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- A novel phenotype in a family with autosomal dominant retinal dystrophy due to c.1430A > G in retinoid isomerohydrolase (RPE65) and c.37C > T in bestrophin 1 (BEST1).Documenta ophthalmologica. Advances in ophthalmology · 2021Article
- Molecular genetics of inherited retinal degenerations in Icelandic patients.Clinical genetics · 2021Article
- Whole exome sequencing reveals putatively novel associations in retinopathies and drusen formation.European journal of human genetics : EJHG · 2021Article
- Inherited Retinal Diseases Due toInternational journal of molecular sciences · 2021Review
- Clinical Perspective: Treating RPE65-Associated Retinal Dystrophy.Molecular therapy : the journal of the American Society of Gene Therapy · 2021Review
Corrections and comments
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Authors and funding
10 authors at 3 institutions in 2 countries.
Funding
Abstract
RPE65 is the essential trans-cis isomerase of the classical retinoid (visual) cycle. Mutations in RPE65 give rise to severe retinal dystrophies, most of which are associated with loss of protein function and recessive inheritance. The only known exception is a c.1430G>A (D477G) mutation that gives rise to dominant retinitis pigmentosa with delayed onset and choroidal and macular involvement. Position 477 is distant from functionally critical regions of RPE65. Hence, the mechanism of D477G pathogenicity remains unclear, although protein misfolding and aggregation mechanisms have been suggested. We characterized a D477G knock-in mouse model which exhibited mild age-dependent changes in retinal structure and function. Immunoblot analysis of protein extracts from the eyes of these knock-in mice demonstrated the presence of ubiquitinated RPE65 and reduced RPE65 expression. We observed an accumulation of retinyl esters in the knock-in mice as well as a delay in rhodopsin regeneration kinetics and diminished electroretinography responses, indicative of RPE65 functional impairment induced by the D477G mutation in vivo. However, a cell line expressing D477G RPE65 revealed protein expression levels, cellular localization and retinoid isomerase activity comparable to cells expressing wild-type protein. Structural analysis of an RPE65 chimera suggested that the D477G mutation does not perturb protein folding or tertiary structure. Instead, the mutation generates an aggregation-prone surface that could induce cellular toxicity through abnormal complex formation as suggested by crystal packing analysis. These results indicate that a toxic gain-of-function induced by the D477G RPE65 substitution may play a role in the pathogenesis of this form of dominant retinitis pigmentosa.
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