ArticleHuman mutation2022
A loss-of-function cysteine mutant in fibulin-3 (EFEMP1) forms aberrant extracellular disulfide-linked homodimers and alters extracellular matrix composition.
Article in Human mutation, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 18 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
- Comprehensive In Silico Analysis of the CXCL12, C55Y Mutation Reveals Structural and Functional Disruption in CXCR4/CXCR7 Signaling.Evolutionary bioinformatics online · 2026Article
- Article
- A Comprehensive Analysis of Novel Variations Associated with Bile Duct Cancer: Insights into Expression, Methylation, and 3D Protein Structure.International journal of molecular sciences · 2025Article
- Multiplex and multimodal mapping of variant effects in secreted proteins via MultiSTEP.Nature structural & molecular biology · 2025Article
- A spectrum of cysteine mutations in fibulin-3 highlight its disulfide bonding complexity and potential to induce ER stress.Scientific reports · 2025Article
- Proteomic analysis of liver fibrosis reveals EFEMP1 as a new modulator of focal adhesion and migration of hepatic stellate cells.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2025Article
- Malignant Pleural Mesothelioma: From Pathophysiology to Innovative Actionable Targets.Cancers · 2025Review
- Multiplex, multimodal mapping of variant effects in secreted proteins.bioRxiv : the preprint server for biology · 2025Article
- Biallelic and monoallelic variants in EFEMP1 can cause a severe and distinct subtype of heritable connective tissue disorder.European journal of human genetics : EJHG · 2024Article
- GSK3 inhibition reduces ECM production and prevents age-related macular degeneration-like pathology.JCI insight · 2024Article
- Exploring ocular fibulin-3 (EFEMP1): Anatomical, age-related, and species perspectives.Biochimica et biophysica acta. Molecular basis of disease · 2024Article
- [Advances in Targeted Therapy for Malignant Pleural Mesothelioma].Zhongguo fei ai za zhi = Chinese journal of lung cancer · 2024Review
- GSK3 inhibition reduces ECM production and prevents age-related macular degeneration-like pathology.bioRxiv : the preprint server for biology · 2023Article
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
Abstract
Fibulin-3 (F3 or EFEMP1) is a disulfide-rich, secreted glycoprotein necessary for maintaining extracellular matrix (ECM) and connective tissue integrity. Three studies have identified distinct autosomal recessive F3 mutations in individuals with Marfan Syndrome-like phenotypes. Herein, we characterize how one of these mutations, c.163T>C; p.Cys55Arg (C55R), disrupts F3 secretion, quaternary structure, and function by forming unique extracellular disulfide-linked homodimers. Dual cysteine mutants suggest that the C55R-induced disulfide species forms because of the new availability of Cys70 on adjacent F3 monomers. Surprisingly, mutation of single cysteines located near Cys55 (i.e., Cys29, Cys42, Cys48, Cys61, Cys70, Cys159, and Cys171) also produced similar extracellular disulfide-linked dimers, suggesting that this is not a phenomenon isolated to the C55R mutant. To assess C55R functionality, F3 knockout (KO) retinal pigmented epithelial (RPE) cells were generated, followed by reintroduction of wild-type (WT) or C55R F3. F3 KO cells produced lower levels of the ECM remodeling enzyme, matrix metalloproteinase 2, and reduced formation of collagen VI ECM filaments, both of which were partially rescued by WT F3 overexpression. However, C55R F3 was unable to compensate for these same ECM-related defects. Our results highlight the unique behavior of particular cysteine mutations in F3 and uncover potential routes to restore C55R F3 loss-of-function.
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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.