ArticleThe Journal of biological chemistry2014
Rescue of enzymatic function for disease-associated RPE65 proteins containing various missense mutations in non-active sites.
Article in The Journal of biological chemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers.
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Who cites it
33 citing papers in PubMed, 40 citations in OpenAlex.
- Long-term effect of gene therapy on Leber's congenital amaurosis.The New England journal of medicine · 2015Trial
- RGR-Mediated Photopic Visual Cycle and Oxidative Stress: Potential Mechanisms for Cone Vision Impairment and Retinal Degeneration in Retinitis Pigmentosa Linked to D1080N-IRBP.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2026Article
- Mild RPE65-Associated Inherited Retinal Dystrophies: A Multimodal Clinical and Genetic Evaluation.Translational vision science & technology · 2025Article
- Higher Throughput Assays for Understanding the Pathogenicity of Variants of Unknown Significance in the RPE65 Gene.Investigative ophthalmology & visual science · 2025Article
- Comprehensive analysis reveals the prognostic and immunological role of PSMD13 in hepatocellular carcinoma.Mammalian genome : official journal of the International Mammalian Genome Society · 2025Article
- Higher throughput assays for understanding the pathogenicity of variants of unknown significance (VUS) in the RPE65 gene.bioRxiv : the preprint server for biology · 2025Article
- Comparative Proteomic Identification of Ram Sperm before and after In Vitro Capacitation.Animals : an open access journal from MDPI · 2024Article
- Gene Supplementation in Mice Heterozygous for the D477G RPE65 Variant Implicated in Autosomal Dominant Retinitis Pigmentosa.Human gene therapy · 2023Article
- Proteostasis Modulation in Germline Missense von Hippel Lindau Disease.Clinical cancer research : an official journal of the American Association for Cancer Research · 2023Article
- Article
- Review
- 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
- Inverse correlation between fatty acid transport protein 4 and vision in Leber congenital amaurosis associated with RPE65 mutation.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
- Impacts of deletion and ichthyosis prematurity syndrome-associated mutations in fatty acid transport protein 4 on the function of RPE65.FEBS letters · 2020Article
- Findings from a Genotyping Study of Over 1000 People with Inherited Retinal Disorders in Ireland.Genes · 2020Article
- Disorders of FZ-CRD; insights towards FZ-CRD folding and therapeutic landscape.Molecular medicine (Cambridge, Mass.) · 2019Review
- Pathogenicity Reclasssification ofGenes · 2019Article
- TBL1Y: a new gene involved in syndromic hearing loss.European journal of human genetics : EJHG · 2019Article
- Generation and Characterization of Induced Pluripotent Stem Cells and Retinal Organoids From a Leber's Congenital Amaurosis Patient With NovelFrontiers in molecular neuroscience · 2019Article
Corrections and comments
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Authors and funding
8 authors at 5 institutions in 1 country.
Funding
Abstract
Over 70 different missense mutations, including a dominant mutation, in RPE65 retinoid isomerase are associated with distinct forms of retinal degeneration; however, the disease mechanisms for most of these mutations have not been studied. Although some mutations have been shown to abolish enzyme activity, the molecular mechanisms leading to the loss of enzymatic function and retinal degeneration remain poorly understood. Here we show that the 26 S proteasome non-ATPase regulatory subunit 13 (PSMD13), a newly identified negative regulator of RPE65, plays a critical role in regulating pathogenicity of three mutations (L22P, T101I, and L408P) by mediating rapid degradation of mutated RPE65s via a ubiquitination- and proteasome-dependent non-lysosomal pathway. These mutant RPE65s were misfolded and formed aggregates or high molecular complexes via disulfide bonds. Interaction of PSMD13 with mutant RPE65s promoted degradation of misfolded but not properly folded mutant RPE65s. Many mutations, including L22P, T101I, and L408P, were mapped on non-active sites. Although their activities were very low, these mutant RPE65s were catalytically active and could be significantly rescued at low temperature, whereas mutant RPE65s with a distinct active site mutation could not be rescued under the same conditions. Sodium 4-phenylbutyrate and glycerol displayed a significant synergistic effect on the low temperature rescue of the mutant RPE65s by promoting proper folding, reducing aggregation, and increasing membrane association. Our results suggest that a low temperature eye mask and sodium 4-phenylbutyrate, a United States Food and Drug Administration-approved oral medicine, may provide a promising "protein repair therapy" that can enhance the efficacy of gene therapy by reducing the cytotoxic effect of misfolded mutant RPE65s.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.