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Updated: Aug 23, 2026
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Published on: April 1, 2022
Biochemical analysis of pathogenic ligand-dependent FGFR2 mutations suggests distinct pathophysiological mechanisms
Omar A Ibrahimi1, Fuming Zhang, Anna V Eliseenkova
1Department of Pharmacology, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA.
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.
Insights
Specific Fibroblast Growth Factor Receptor 2 (FGFR2) mutations cause craniosynostosis and limb defects by altering ligand binding. These FGFR2 mutations increase binding affinity and specificity, leading to distinct pathologies like Apert syndrome.
Area of Science:
- Molecular biology
- Genetics
- Biophysics
Background:
- Gain-of-function missense mutations in Fibroblast Growth Factor Receptor 2 (FGFR2) cause craniosynostosis syndromes such as Apert syndrome (AS), Pfeiffer syndrome (PS), and Crouzon syndrome (CS).
- Certain FGFR2 mutations, including AS and PS mutations, retain ligand-dependency and are linked to severe limb abnormalities.
- A double mutation (S252L/A315S) in FGFR2 causes syndactyly without craniosynostosis.
Purpose of the Study:
- To investigate the impact of specific FGFR2 mutations (AS, PS, and double mutations) on ligand binding affinity and specificity.
- To elucidate the molecular mechanisms underlying craniosynostosis and limb pathology associated with these FGFR2 mutations.
Main Methods:
- Surface plasmon resonance was employed to analyze FGFR2 ligand binding.
- Structural and biophysical analyses were conducted on FGFR2b mutations.
Main Results:
- AS and D321A PS mutations increased FGFR2c binding affinity to cranial suture FGFs.
- All four pathogenic mutations disrupted FGFR2c ligand binding specificity, allowing FGF10 binding.
- AS mutations in FGFR2b also enhanced and altered ligand binding affinity and specificity.
Conclusions:
- Increased binding of mutant FGFR2c to multiple FGFs may cause craniosynostosis.
- Mutant FGFR2c binding to FGF10 is proposed to cause severe limb pathology.
- Altered FGFR2b signaling due to AS mutations might explain dermatological manifestations in AS.
