ArticleHuman mutation2019
Aberrant RNA splicing is the major pathogenic effect in a knock-in mouse model of the dominantly inherited c.1430A>G human RPE65 mutation.
Article in Human mutation, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
21 citing papers in PubMed, 24 citations in OpenAlex.
- Dynamic Inner Blood Retina Barrier Disruption in Retinitis Pigmentosa.Investigative ophthalmology & visual science · 2025Article
- Alternative Splicing Dysregulation in Retinitis Pigmentosa: Pathogenic Mechanisms and Therapeutic Opportunities.Biomolecules · 2025Review
- RPE65 Variant p.(E519K) Causes a Novel Dominant Adult-Onset Maculopathy in 83 Affected Individuals.Investigative ophthalmology & visual science · 2025Article
- Gene Therapy for Retinitis Pigmentosa: Current Challenges and New Progress.Biomolecules · 2024Review
- Dual AAV-based PCDH15 gene therapy achieves sustained rescue of visual function in a mouse model of Usher syndrome 1F.Molecular therapy : the journal of the American Society of Gene Therapy · 2023Article
- Gene Supplementation in Mice Heterozygous for the D477G RPE65 Variant Implicated in Autosomal Dominant Retinitis Pigmentosa.Human gene therapy · 2023Article
- Environmental Light Has an Essential Effect on the Disease Expression in a Dominant RPE65 Mutation.Advances in experimental medicine and biology · 2023Article
- Carrier frequency and incidence estimation of RPE65-associated inherited retinal diseases in East Asian population by population database-based analysis.Orphanet journal of rare diseases · 2022Article
- Genetic dissection of non-syndromic retinitis pigmentosa.Indian journal of ophthalmology · 2022Review
- Retinal pigment epithelium 65 kDa protein (RPE65): An update.Progress in retinal and eye research · 2022Review
- 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
- Proposed therapy, developed in aeLife · 2021Article
- 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
- Whole exome sequencing reveals putatively novel associations in retinopathies and drusen formation.European journal of human genetics : EJHG · 2021Article
- Clinical Perspective: Treating RPE65-Associated Retinal Dystrophy.Molecular therapy : the journal of the American Society of Gene Therapy · 2021Review
- Review
- Review
- Phenotypic expansion of autosomal dominant retinitis pigmentosa associated with the D477G mutation inCold Spring Harbor molecular case studies · 2020Article
- Findings from a Genotyping Study of Over 1000 People with Inherited Retinal Disorders in Ireland.Genes · 2020Article
- Advanced late-onset retinitis pigmentosa with dominant-acting D477G RPE65 mutation is responsive to oral synthetic retinoid therapy.BMJ open ophthalmology · 2020Article
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Authors and funding
14 authors at 3 institutions in 1 country.
Funding
Abstract
Human RPE65 mutations cause a spectrum of retinal dystrophies that result in blindness. While RPE65 mutations have been almost invariably recessively inherited, a c.1430A>G (p.(D477G)) mutation has been reported to cause autosomal dominant retinitis pigmentosa (adRP). To study the pathogenesis of this human mutation, we have replicated the mutation in a knock-in (KI) mouse model using CRISPR/Cas9-mediated genome editing. Significantly, in contrast to human patients, heterozygous KI mice do not exhibit any phenotypes in visual function tests. When raised in regular vivarium conditions, homozygous KI mice display relatively undisturbed visual functions with minimal retinal structural changes. However, KI/KI mouse retinae are more sensitive to light exposure and exhibit signs of degenerative features when subjected to light stress. We find that instead of merely producing a missense mutant protein, the A>G nucleotide substitution greatly affects appropriate splicing of Rpe65 mRNA by generating an ectopic splice site in comparable context to the canonical one, thereby disrupting RPE65 protein expression. Similar splicing defects were also confirmed for the human RPE65 c.1430G mutant in an in vitro Exontrap assay. Our data demonstrate that a splicing defect is associated with c.1430G pathogenesis, and therefore provide insights in the therapeutic strategy for human patients.
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