ArticleHuman molecular genetics2018
Localization and functional characterization of the p.Asn965Ser (N965S) ABCA4 variant in mice reveal pathogenic mechanisms underlying Stargardt macular degeneration.
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.
- Loss of ABCA4 from photoreceptor discs is associated with glial transcriptomic changes in retinal organoids.Stem cells (Dayton, Ohio) · 2026Article
- Abca4 Knockdown in the Cone-Rich Rodent Psammomys Obesus Leads to Stargardt's Disease-Like Progressive Retinal Degeneration.Investigative ophthalmology & visual science · 2026Article
- Characterization of the Subclinical Perilesional Zone in the Macula of Early-Stage ABCA4 Disease.Translational vision science & technology · 2025Article
- ABCA4-mutant human retinal organoids sequencing reveals organoids application in inherited retinal diseases.Experimental eye research · 2025Article
- Investigation of ABCA4 Missense Variants and Potential Small Molecule Rescue in Retinal Organoids.Investigative ophthalmology & visual science · 2025Article
- Generation of a compound heterozygous ABCA4 rat model with pathological features of STGD1.Human molecular genetics · 2025Article
- Retinal gene therapy for Stargardt disease with dual AAV intein vectors is both safe and effective in large animal models.Science advances · 2025Article
- iPSC-derived retinal pigment epithelium: an in vitro platform to reproduce key cellular phenotypes and pathophysiology of retinal degenerative diseases.Stem cells translational medicine · 2025Review
- Preclinical assessment of splicing modulation therapy for ABCA4 variant c.768G>T in Stargardt disease.Communications medicine · 2025Article
- Assessment of ABCA4 Genetic Variants: Current Landscape and Future Prospects.Advances in experimental medicine and biology · 2025Review
- Abca4, mutated in Stargardt disease, is required for structural integrity of cone outer segments.Disease models & mechanisms · 2025Article
- 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
- Interruption of the visual cycle in a novel animal model induces progressive vision loss resembling Stargardts Disease.Scientific reports · 2024Article
- A Proximity Complementation Assay to Identify Small Molecules That Enhance the Traffic of ABCA4 Misfolding Variants.International journal of molecular sciences · 2024Article
- Role of theInternational journal of molecular sciences · 2023Article
- Protein modeling and in silico analysis to assess pathogenicity ofMolecular vision · 2023Article
- Rare missense mutations in ABCA7 might increase Alzheimer's disease risk by plasma membrane exclusion.Acta neuropathologica communications · 2022Article
- Clinical Observation and Genotype-Phenotype Analysis of ABCA4- Related Hereditary Retinal Degeneration before Gene Therapy.Current gene therapy · 2022Article
- Therapy Approaches for Stargardt Disease.Biomolecules · 2021Review
- Cis-acting modifiers in the ABCA4 locus contribute to the penetrance of the major disease-causing variant in Stargardt disease.Human molecular genetics · 2021Article
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4 authors.
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Abstract
ABCA4 is a member of the superfamily of ATP-binding cassette (ABC) proteins that transports N-retinylidene-phosphatidylethanolamine (N-Ret-PE) across outer segment disc membranes thereby facilitating the removal of potentially toxic retinoid compounds from photoreceptor cells. Mutations in the gene encoding ABCA4 are responsible for Stargardt disease (STGD1), an autosomal recessive retinal degenerative disease that causes severe vision loss. To define the molecular basis for STGD1 associated with the p.Asn965Ser (N965S) mutation in the Walker A motif of nucleotide binding domain 1 (NBD1), we generated a p.Asn965Ser knockin mouse and compared the subcellular localization and molecular properties of the disease variant with wild-type (WT) ABCA4. Here, we show that the p.Asn965Ser ABCA4 variant expresses at half the level of WT ABCA4, partially mislocalizes to the endoplasmic reticulum (ER) of photoreceptors, is devoid of N-Ret-PE activated ATPase activity, and causes an increase in autofluorescence and the bisretinoid A2E associated with lipofuscin deposits in retinal pigment epithelial cells as found in Stargardt patients and Abca4 knockout mice. We also show for the first time that a significant fraction of WT ABCA4 is retained in the inner segment of photoreceptors. On the basis of these studies we conclude that loss in substrate-dependent ATPase activity and protein misfolding are mechanisms underlying STGD1 associated with the p.Asn965Ser mutation in ABCA4. Functional and molecular modeling studies further suggest that similar pathogenic mechanisms are responsible for Tangiers disease associated with the p.Asn935Ser (N935S) mutation in the NBD1 Walker A motif of ABCA1.
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