Loss of fibroblast growth factor receptor 2 ligand-binding specificity in Apert syndrome

Craniosynostosis syndromes are autosomal dominant human skeletal diseases t hat result from various mutations in fibroblast growth factor receptor gene s (Fgfrs). Apert syndrome (AS) is one of the most severe craniosynostosis s yndromes and is associated with severe syndactyly of the hands and feet and with central nervous system malformations. AS is caused by specific missen se mutations in one of two adjacent amino acid residues (S252W or P253R) in the highly conserved region linking Ig-like domains II and III of FGFR2. H ere we demonstrate that these mutations break one of the cardinal rules gov erning ligand specificity of FGFR2. We show that the S252W mutation allows the mesenchymal splice form of FGFR2 (FGFR2c) to bind and to be activated b y the mesenchymally expressed ligands FGF7 or FGF10 and the epithelial spli ce form of FGFR2 (FGFR2b) to be activated by FGF2, FGF6, and FGF9. These da ta demonstrate loss of ligand specificity of FGFR2 with retained ligand dep endence for receptor activation. These data suggest that the severe phenoty pes of AS likely result from ectopic ligand-dependent activation of FGFR2.