ArticleHuman molecular genetics2004
Biochemical analysis of pathogenic ligand-dependent FGFR2 mutations suggests distinct pathophysiological mechanisms for craniofacial and limb abnormalities.
Article in Human molecular genetics, 2004. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 76 papers.
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Who cites it
76 citing papers in PubMed, 149 citations in OpenAlex.
- Quantification of facial skeletal shape variation in fibroblast growth factor receptor-related craniosynostosis syndromes.Birth defects research. Part A, Clinical and molecular teratology · 2014Trial
- Increased thermal stability of FGF10 leads to ectopic signaling during development.Cellular and molecular life sciences : CMLS · 2025Article
- Quantitative and qualitative differences in the activation of a fibroblast growth factor receptor by different FGF ligands.Cytokine & growth factor reviews · 2024Review
- Excessive osteoclast activation by osteoblast paracrine factor RANKL is a major cause of the abnormal long bone phenotype in Apert syndrome model mice.Journal of cellular physiology · 2022Article
- Signaling Pathway and Small-Molecule Drug Discovery of FGFR: A Comprehensive Review.Frontiers in chemistry · 2022Review
- FGFR signaling and endocrine resistance in breast cancer: Challenges for the clinical development of FGFR inhibitors.Biochimica et biophysica acta. Reviews on cancer · 2021Review
- Acne Syndromes and Mosaicism.Biomedicines · 2021Review
- Activation of FGFR2 Signaling Suppresses BRCA1 and Drives Triple-Negative Mammary Tumorigenesis That is Sensitive to Immunotherapy.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2021Article
- A cancer mutation promotes EphA4 oligomerization and signaling by altering the conformation of the SAM domain.The Journal of biological chemistry · 2021Article
- Genotype-Phenotype Correlation of Tracheal Cartilaginous Sleeves and Fgfr2 Mutations in Mice.The Laryngoscope · 2021Article
- Article
- Inhibitory effects of msFGFR2c on the epithelial-to-mesenchymal transition of AE2 cells in pulmonary fibrosis.Biotechnology letters · 2020Article
- Article
- Evaluation of a cell model expressing βKlotho for screening FGF21 analogues.Cytotechnology · 2019Article
- Review
- Nuclear Fibroblast Growth Factor Receptor Signaling in Skeletal Development and Disease.Current osteoporosis reports · 2019Review
- PIN1 is a new therapeutic target of craniosynostosis.Human molecular genetics · 2018Article
- Midface and upper airway dysgenesis in FGFR2-related craniosynostosis involves multiple tissue-specific and cell cycle effects.Development (Cambridge, England) · 2018Article
- FGF binding proteins (FGFBPs): Modulators of FGF signaling in the developing, adult, and stressed nervous system.Biochimica et biophysica acta. Molecular basis of disease · 2018Review
- Chemoresistance and targeting of growth factors/cytokines signalling pathways: towards the development of effective therapeutic strategy for endometrial cancer.American journal of cancer research · 2018Review
16 more citing papers are in PubMed but not listed here.
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
Abstract
Gain-of-function missense mutations in FGF receptor 2 (FGFR2) are responsible for a variety of craniosynostosis syndromes including Apert syndrome (AS), Pfeiffer syndrome (PS) and Crouzon syndrome (CS). Unlike the majority of FGFR2 mutations, S252W and P253R AS mutations and a D321A PS mutation retain ligand-dependency and are also associated with severe limb pathology. In addition, a recently identified ligand-dependent S252L/A315S double mutation in FGFR2 was shown to cause syndactyly in the absence of craniosynostosis. Here, we analyze the effect of the canonical AS mutations, the D321A PS mutation and the S252L/A315S double mutation on FGFR2 ligand binding affinity and specificity using surface plasmon resonance. Both AS mutations and the D321A PS mutation, but not the S252L/A315S double mutation, increase the binding affinity of FGFR2c to multiple FGFs expressed in the cranial suture. Additionally, all four pathogenic mutations also violate FGFR2c ligand binding specificity and enable this receptor to bind FGF10. Based on our data, we propose that an increase in mutant FGFR2c binding to multiple FGFs results in craniosynostosis, whereas binding of mutant FGFR2c to FGF10 results in severe limb pathology. Structural and biophysical analysis shows that AS mutations in FGFR2b also enhance and violate FGFR2b ligand binding affinity and specificity, respectively. We suggest that elevated AS mutant FGFR2b signaling may account for the dermatological manifestations of AS.
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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.