ArticleHuman molecular genetics2015
Protein misfolding and the pathogenesis of ABCA4-associated retinal degenerations.
Article in Human molecular genetics, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 70 papers.
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Who cites it
70 citing papers in PubMed, 100 citations in OpenAlex.
- Abca4 Knockdown in the Cone-Rich Rodent Psammomys Obesus Leads to Stargardt's Disease-Like Progressive Retinal Degeneration.Investigative ophthalmology & visual science · 2026Article
- More insights from Abca4The Journal of biological chemistry · 2026Article
- Genetic Correlates of Phenotypic Variability in c.5882G>A p.(Gly1961Glu)-Associated Stargardt Disease.Investigative ophthalmology & visual science · 2026Article
- Rhodopsin molecular evolution from mouse to human phenylalanine 88 to leucine substitution enhances thermal stability and post-activation decay.Scientific reports · 2026Article
- ABCA4-mutant human retinal organoids sequencing reveals organoids application in inherited retinal diseases.Experimental eye research · 2025Article
- Characterization of the Subclinical Perilesional Zone in the Macula of Early-Stage ABCA4 Disease.Translational vision science & technology · 2025Article
- Dysregulated DNA Methylation inInternational journal of molecular sciences · 2025Article
- Decoding the Genetic Puzzle of Inherited Retinal Dystrophies: Novel Insights From a Turkish Cohort.Clinical genetics · 2025Article
- Insights into rhodopsin molecular evolution from mice with "humanized" Phe-88 to Leu substitution.Research square · 2025Article
- Stargardt's Connected Research Network Inaugural Meeting: Landscape Review and Horizon Scanning of Stargardt Disease.Translational vision science & technology · 2025Review
- Photoreceptor Disease at Ambiguous Transition Zones in Inherited Retinal Degenerations.Translational vision science & technology · 2025Article
- Investigation of ABCA4 Missense Variants and Potential Small Molecule Rescue in Retinal Organoids.Investigative ophthalmology & visual science · 2025Article
- Advances and therapeutic opportunities in visual cycle modulation.Progress in retinal and eye research · 2025Review
- Polydatin and Nicotinamide Prevent Iron Accumulation and Lipid Peroxidation in Cellular Models of Mitochondrial Diseases.Antioxidants (Basel, Switzerland) · 2025Article
- Future applications of fluorescence lifetime imaging ophthalmoscopy in neuro-ophthalmology, neurology, and neurodegenerative conditions.Frontiers in neurology · 2025Review
- Deciphering the impact of ABCA4 genetic variants of unknown significance in inherited retinal disease through computational and functional approaches.Advances in protein chemistry and structural biology · 2025Review
- Abca4, mutated in Stargardt disease, is required for structural integrity of cone outer segments.Disease models & mechanisms · 2025Article
- Assessment of ABCA4 Genetic Variants: Current Landscape and Future Prospects.Advances in experimental medicine and biology · 2025Review
- Interruption of the visual cycle in a novel animal model induces progressive vision loss resembling Stargardts Disease.Scientific reports · 2024Article
- Article
10 more citing papers are in PubMed but not listed here.
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Authors and funding
13 authors at 5 institutions in 1 country.
Funding
Abstract
Mutations in the ABCA4 gene are a common cause of autosomal recessive retinal degeneration. All mouse models to date are based on knockouts of Abca4, even though the disease is often caused by missense mutations such as the complex allele L541P;A1038V (PV). We now show that the PV mutation causes severe human disease whereas the V mutation alone causes mild disease. Mutant ABCA4 proteins expressed heterologously in mammalian cells retained normal cellular localization. However, basal and all-trans-retinal-stimulated ATPase activities were reduced substantially for P and PV but only mildly for V. Electron microscopy revealed marked structural changes and misfolding for the P and PV mutants but few changes for the V mutant, consistent with the disease severity difference in patients. We generated Abca4(PV/PV) knock-in mice homozygous for the complex PV allele to investigate the effects of this misfolding mutation in vivo. Mutant ABCA4 RNA levels approximated WT ABCA4 RNA levels but, surprisingly, only trace amounts of mutant ABCA4 protein were noted in the retina. RNA sequencing of WT, Abca4(-/-) and Abca4(PV/PV) mice revealed mild gene expression alterations in the retina and RPE. Similar to Abca4(-/-) mice, Abca4(PV/PV) mice showed substantial A2E and lipofuscin accumulation in their RPE cells but no retinal degeneration up to 12 months of age. Thus, rapid degradation of this large misfolded mutant protein in mouse retina caused little detectable photoreceptor degeneration. These findings suggest likely differences in the unfolded protein response between murine and human photoreceptors and support development of therapies directed at increasing this capability in patients.
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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.