Apert syndrome mutations in fibroblast growth factor receptor 2 exhibit increased affinity for FGF ligand

Dominantly acting mutations of the fibroblast growth factor (FGF) receptor2 (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 andPro253Arg, predicted to lie in the linker region between IgII and IgIII ofthe FGFR2 ligand-binding domain. We have analysed the interaction of FGFligands with wild-type and Apert- type mutant FGFR2 ectodomains insolution. Wild-type and Apert-type receptors form a complex with FGFligands with a stoichiometry of 2:2 (ligand:receptor). The kinetics andspecificity of ligand binding to wild-type and Apert mutant receptors havebeen analysed using surface plasmon resonance techniques. This reveals thatApert mutations, compared with wild-type, exhibit a selective decrease inthe dissociation kinetics of FGF2, but not of other FGF ligands examined.In contrast, the substitution Ser252Leu in FGFR2, previously observed inseveral asymptomatic individuals, exhibited wild-type kinetics. Thesefindings indicate that Apert syndrome arises as a result of increasedaffinity of mutant receptors for specific FGF ligands which leads toactivation of signalling under conditions where availability of ligand islimiting.