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Apert syndrome mutations in fibroblast growth factor receptor 2 exhibit increased affinity for FGF ligand.
Hum Mol Genet. 1998 Sep; 7(9):1475-83.HM

Abstract

Dominantly acting mutations of the fibroblast growth factor (FGF) receptor 2 (FGFR2) gene have been implicated in various craniosynostosis syndromes. Apert syndrome, characterized in addition by syndactyly of the limbs, involves specific mutations at two adjacent residues, Ser252Trp and Pro253Arg, predicted to lie in the linker region between IgII and IgIII of the FGFR2 ligand-binding domain. We have analysed the interaction of FGF ligands with wild-type and Apert-type mutant FGFR2 ectodomains in solution. Wild-type and Apert-type receptors form a complex with FGF ligands with a stoichiometry of 2:2 (ligand:receptor). The kinetics and specificity of ligand binding to wild-type and Apert mutant receptors have been analysed using surface plasmon resonance techniques. This reveals that Apert mutations, compared with wild-type, exhibit a selective decrease in the dissociation kinetics of FGF2, but not of other FGF ligands examined. In contrast, the substitution Ser252Leu in FGFR2, previously observed in several asymptomatic individuals, exhibited wild-type kinetics. These findings indicate that Apert syndrome arises as a result of increased affinity of mutant receptors for specific FGF ligands which leads to activation of signalling under conditions where availability of ligand is limiting.

Authors+Show Affiliations

School of Biochemistry, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

9700203

Citation

Anderson, J, et al. "Apert Syndrome Mutations in Fibroblast Growth Factor Receptor 2 Exhibit Increased Affinity for FGF Ligand." Human Molecular Genetics, vol. 7, no. 9, 1998, pp. 1475-83.
Anderson J, Burns HD, Enriquez-Harris P, et al. Apert syndrome mutations in fibroblast growth factor receptor 2 exhibit increased affinity for FGF ligand. Hum Mol Genet. 1998;7(9):1475-83.
Anderson, J., Burns, H. D., Enriquez-Harris, P., Wilkie, A. O., & Heath, J. K. (1998). Apert syndrome mutations in fibroblast growth factor receptor 2 exhibit increased affinity for FGF ligand. Human Molecular Genetics, 7(9), 1475-83.
Anderson J, et al. Apert Syndrome Mutations in Fibroblast Growth Factor Receptor 2 Exhibit Increased Affinity for FGF Ligand. Hum Mol Genet. 1998;7(9):1475-83. PubMed PMID: 9700203.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Apert syndrome mutations in fibroblast growth factor receptor 2 exhibit increased affinity for FGF ligand. AU - Anderson,J, AU - Burns,H D, AU - Enriquez-Harris,P, AU - Wilkie,A O, AU - Heath,J K, PY - 1998/8/13/pubmed PY - 1998/8/13/medline PY - 1998/8/13/entrez SP - 1475 EP - 83 JF - Human molecular genetics JO - Hum Mol Genet VL - 7 IS - 9 N2 - Dominantly acting mutations of the fibroblast growth factor (FGF) receptor 2 (FGFR2) gene have been implicated in various craniosynostosis syndromes. Apert syndrome, characterized in addition by syndactyly of the limbs, involves specific mutations at two adjacent residues, Ser252Trp and Pro253Arg, predicted to lie in the linker region between IgII and IgIII of the FGFR2 ligand-binding domain. We have analysed the interaction of FGF ligands with wild-type and Apert-type mutant FGFR2 ectodomains in solution. Wild-type and Apert-type receptors form a complex with FGF ligands with a stoichiometry of 2:2 (ligand:receptor). The kinetics and specificity of ligand binding to wild-type and Apert mutant receptors have been analysed using surface plasmon resonance techniques. This reveals that Apert mutations, compared with wild-type, exhibit a selective decrease in the dissociation kinetics of FGF2, but not of other FGF ligands examined. In contrast, the substitution Ser252Leu in FGFR2, previously observed in several asymptomatic individuals, exhibited wild-type kinetics. These findings indicate that Apert syndrome arises as a result of increased affinity of mutant receptors for specific FGF ligands which leads to activation of signalling under conditions where availability of ligand is limiting. SN - 0964-6906 UR - https://www.unboundmedicine.com/medline/citation/9700203/Apert_syndrome_mutations_in_fibroblast_growth_factor_receptor_2_exhibit_increased_affinity_for_FGF_ligand_ L2 - https://academic.oup.com/hmg/article-lookup/doi/10.1093/hmg/7.9.1475 DB - PRIME DP - Unbound Medicine ER -