ArticleThe Journal of biological chemistry2011
An essential role of the cysteine-rich domain of FZD4 in Norrin/Wnt signaling and familial exudative vitreoretinopathy.
Article in The Journal of biological chemistry, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed, 41 citations in OpenAlex.
- A novel variant p.Y250C of FZD4 influences Norrine/β-catenin signaling pathway that associates with familial exudative vitreoretinopathy (FEVR).Scientific reports · 2026Article
- Gene Variant Spectrum in Probands With Familial Exudative Vitreoretinopathy Using an Expanded Panel.Investigative ophthalmology & visual science · 2025Article
- Frizzled receptors: gatekeepers of Wnt signaling in development and disease.Frontiers in cell and developmental biology · 2025Review
- Identification of Novel FZD4 Mutations in Familial Exudative Vitreoretinopathy and Investigating the Pathogenic Mechanisms of FZD4 Mutations.Investigative ophthalmology & visual science · 2024Article
- Modification of maternally defined H3K4me3 regulates the inviability of interspecificScience advances · 2023Article
- Cellular and Molecular Mechanisms of Pathogenesis Underlying Inherited Retinal Dystrophies.Biomolecules · 2023Review
- FZD4 in a Large Chinese Population With Familial Exudative Vitreoretinopathy: Molecular Characteristics and Clinical Manifestations.Investigative ophthalmology & visual science · 2022Article
- Ocular phenotype and genetical analysis in patients with retinopathy of prematurity.BMC ophthalmology · 2022Article
- Decrease ofFrontiers in medicine · 2022Article
- Role ofBioMed research international · 2020Article
- Disorders of FZ-CRD; insights towards FZ-CRD folding and therapeutic landscape.Molecular medicine (Cambridge, Mass.) · 2019Review
- Molecular evolutionary and structural analysis of familial exudative vitreoretinopathy associated FZD4 gene.BMC evolutionary biology · 2019Article
- Familial Exudative Vitreoretinopathy-Related Disease-Causing Genes and Norrin/Journal of ophthalmology · 2019Review
- Variable reduction in Norrin signaling activity caused by novel mutations inMolecular vision · 2019Article
- Functional dissection of the N-terminal extracellular domains of Frizzled 6 reveals their roles for receptor localization and Dishevelled recruitment.The Journal of biological chemistry · 2018Article
- WNT Signaling in Cardiac and Vascular Disease.Pharmacological reviews · 2018Review
- Molecular genetics and targeted therapy of WNT-related human diseases (Review).International journal of molecular medicine · 2017Article
- Genotype-Phenotype Characterization of Novel Variants in Six Italian Patients with Familial Exudative Vitreoretinopathy.Journal of ophthalmology · 2017Article
- Mutation spectrum of the FZD-4, TSPAN12 AND ZNF408 genes in Indian FEVR patients.BMC ophthalmology · 2016Article
- Identification and functional analysis of novel FZD4 mutations in Han Chinese with familial exudative vitreoretinopathy.Scientific reports · 2015Article
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Authors and funding
11 authors at 7 institutions in 3 countries.
Funding
Abstract
The Wnt pathway plays important yet diverse roles in health and disease. Mutations in the Wnt receptor FZD4 gene have been confirmed to cause familial exudative vitreoretinopathy (FEVR). FEVR is characterized by incomplete vascularization of the peripheral retina, which can lead to vitreous bleeding, tractional retinal detachment, and blindness. We screened for mutations in the FZD4 gene in five families with FEVR and identified five mutations (C45Y, Y58C, W226X, C204R, and W496X), including three novel mutations (C45Y, Y58C, and W226X). In the retina, Norrin serves as a ligand and binds to FZD4 to activate the Wnt signaling pathway in normal angiogenesis and vascularization. The cysteine-rich domain (CRD) of FZD4 has been shown to play a critical role in Norrin-FZD4 binding. We investigated the effect of mutations in the FZD4 CRD in Norrin binding and signaling in vitro and in vivo. Wild-type and mutant FZD4 proteins were assayed for Norrin binding and Norrin-dependent activation of the canonical Wnt pathway by cell-surface and overlay binding assays and luciferase reporter assays. In HEK293 transfection studies, C45Y, Y58C, and C204R mutants did not bind to Norrin and failed to transduce FZD4-mediated Wnt/β-catenin signaling. In vivo studies using Xenopus embryos showed that these FZD4 mutations disrupt Norrin/β-catenin signaling as evidenced by decreased Siamois and Xnr3 expression. This study identified a new class of FZD4 gene mutations in human disease and demonstrates a critical role of the CRD in Norrin binding and activation of the β-catenin pathway.
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