APERT SYNDROME MUTATIONS IN FIBROBLAST-GROWTH-FACTOR RECEPTOR-2 EXHIBIT INCREASED AFFINITY FOR FGF LIGAND

Dominantly acting mutations of the fibroblast growth factor (FGF) rece ptor 2 (FGFR2) gene have been implicated in various craniosynostosis s yndromes, Apert syndrome, characterized in addition by syndactyly of t he limbs, involves specific mutations at two adjacent residues, Ser252 Trp and Pro253Arg, predicted to lie in the linker region between IgII and IgIII of the FGFR2 ligand-binding domain. We have analysed the int eraction of FGF ligands with wild-type and Apert-type mutant FGFR2 ect odomains in solution, Wild-type and Apert-type receptors form a comple x with FGF ligands with a stoichiometry of 2:2 (ligand:receptor). The kinetics and specificity of ligand binding to wild-type and Apert muta nt receptors have been analysed using surface plasmon resonance techni ques. This reveals that Apert mutations, compared with wild-type, exhi bit a selective decrease in the dissociation kinetics of FGF2, but not of other FGF ligands examined, In contrast, the substitution Ser252Le u in FGFR2, previously observed in several asymptomatic individuals, e xhibited wild-type kinetics, These findings indicate that Apert syndro me arises as a result of increased affinity of mutant receptors for sp ecific FGF ligands which leads to activation of signalling under condi tions where availability of ligand is limiting.