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Human Molecular Genetics Advance Access originally published online on July 28, 2004
Human Molecular Genetics 2004 13(19):2313-2324; doi:10.1093/hmg/ddh235
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Human Molecular Genetics, Vol. 13, No. 19 © Oxford University Press 2004; all rights reserved

Biochemical analysis of pathogenic ligand-dependent FGFR2 mutations suggests distinct pathophysiological mechanisms for craniofacial and limb abnormalities

Omar A. Ibrahimi1, Fuming Zhang2, Anna V. Eliseenkova1, Nobuyuki Itoh3, Robert J. Linhardt2 and Moosa Mohammadi1,*

1Department of Pharmacology, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA, 2Departments of Chemistry, Chemical Biology and Biological Engineering, Rensselaer Polytechnic Institute, Troy, NY 12180, USA and 3Department of Genetic Biochemistry, Kyoto University Graduate School of Pharmaceutical Sciences, Yoshida-Shimoadachi, Kyoto 606-8501, Japan

Received May 18, 2004; Accepted July 12, 2004

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.

* To whom correspondence should be addressed at: Moosa Mohammadi, NYU School of Medicine, 550 First Avenue, MSB 425, Department of Pharmacology, New York, NY 10016, USA. Tel: +1 2122632907; Fax: +1 2122637133; Email: mohammad{at}saturn.med.nyu.edu


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