ArticleHuman molecular genetics2015
A local complement response by RPE causes early-stage macular degeneration.
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 46 papers.
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Who cites it
46 citing papers in PubMed, 77 citations in OpenAlex.
- Interactions Between Epidermal Growth Factor-Containing Fibulin-Like Extracellular Matrix Protein 1 and Tissue Inhibitor of Metalloproteinases-3 and Relevance to Age-Related Macular Degeneration.Ophthalmology science · 2026Review
- Antisense oligonucleotide allele-specific targeting of EFEMP1 in a patient-derived model of Doyne honeycomb retinal dystrophy.Molecular therapy. Nucleic acids · 2026Article
- Genetic removal of Nlrp3 protects against age-related and R345W Efemp1-induced basal laminar deposit formation.Cell death & disease · 2025Article
- Human iPSC-based disease modeling studies identify a common mechanistic defect and potential therapies for AMD and related macular dystrophies.Developmental cell · 2024Article
- GSK3 inhibition reduces ECM production and prevents age-related macular degeneration-like pathology.JCI insight · 2024Article
- GSK3 inhibition reduces ECM production and prevents age-related macular degeneration-like pathology.bioRxiv : the preprint server for biology · 2023Article
- Distinct Phenotypic Consequences of Pathogenic Mutants Associated with Late-Onset Retinal Degeneration.The American journal of pathology · 2023Article
- Bruch's Membrane: A Key Consideration with Complement-Based Therapies for Age-Related Macular Degeneration.Journal of clinical medicine · 2023Review
- Qihuang Granule protects the retinal pigment epithelium from oxidative stress via regulation of the alternative complement pathway.BMC complementary medicine and therapies · 2023Article
- Altered zinc homeostasis in a primary cell culture model of the retinal pigment epithelium.Frontiers in nutrition · 2023Article
- FoxP3 expression by retinal pigment epithelial cells: transcription factor with potential relevance for the pathology of age-related macular degeneration.Journal of neuroinflammation · 2022Article
- Cell culture models to study retinal pigment epithelium-related pathogenesis in age-related macular degeneration.Experimental eye research · 2022Review
- Sex and Age-Related Differences in Complement Factors Among Patients With Intermediate Age-Related Macular Degeneration.Translational vision science & technology · 2022Article
- EFEMP1 rare variants cause familial juvenile-onset open-angle glaucoma.Human mutation · 2022Article
- AMD-Like Substrate Causes Epithelial Mesenchymal Transition in iPSC-Derived Retinal Pigment Epithelial Cells Wild Type but NotInternational journal of molecular sciences · 2021Article
- Targeting complement components C3 and C5 for the retina: Key concepts and lingering questions.Progress in retinal and eye research · 2021Review
- Complement System and Potential Therapeutics in Age-Related Macular Degeneration.International journal of molecular sciences · 2021Review
- Complement C5 is not critical for the formation of sub-RPE deposits in Efemp1 mutant mice.Scientific reports · 2021Article
- Impaired cholesterol efflux in retinal pigment epithelium of individuals with juvenile macular degeneration.American journal of human genetics · 2021Article
- The complement system in age-related macular degeneration.Cellular and molecular life sciences : CMLS · 2021Review
Corrections and comments
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Authors and funding
3 authors at 2 institutions in 2 countries.
Funding
Abstract
Inherited and age-related macular degenerations (AMDs) are important causes of vision loss. An early hallmark of these disorders is the formation of sub-retinal pigment epithelium (RPE) basal deposits. A role for the complement system in MDs was suggested by genetic association studies, but direct functional connections between alterations in the complement system and the pathogenesis of MD remain to be defined. We used primary RPE cells from a mouse model of inherited MD due to a p.R345W mutation in EGF-containing fibulin-like extracellular matrix protein 1 (EFEMP1) to investigate the role of the RPE in early MD pathogenesis. Efemp1(R345W) RPE cells recapitulate the basal deposit formation observed in vivo by producing sub-RPE deposits in vitro. The deposits share features with basal deposits, and their formation was mediated by EFEMP1(R345W) or complement component 3a (C3a), but not by complement component 5a (C5a). Increased activation of complement appears to occur in response to an abnormal extracellular matrix (ECM), generated by the mutant EFEMP1(R345W) protein and reduced ECM turnover due to inhibition of matrix metalloproteinase 2 by EFEMP1(R345W) and C3a. Increased production of C3a also stimulated the release of cytokines such as interleukin (IL)-6 and IL-1B, which appear to have a role in deposit formation, albeit downstream of C3a. These studies provide the first direct indication that complement components produced locally by the RPE are involved in the formation of basal deposits. Furthermore, these results suggest that C3a generated by RPE is a potential therapeutic target for the treatment of EFEMP1-associated MD as well as AMD.
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