THE MUTATIONS IN FGFR2-ASSOCIATED CRANIOSYNOSTOSES ARE CLUSTERED IN 5STRUCTURAL ELEMENTS OF IMMUNOGLOBULIN-LIKE DOMAIN-III OF THE RECEPTOR

Exons 5 and 7 of the fibroblast growth factor receptor 2 (FGFR2) gene code for immunoglobulin-like domain III (IgIII) and for the region con necting the second and the third Ig domain of the receptor. Numerous m utations in these two exons have been shown to cause various craniosyn ostotic syndromes. Here, we describe three previously unrecognized mut ations at amino acid positions 276, 301, and 314, in one nonspecific c raniosynostosis and in two Crouzon patients. We also present a polypep tide model of IgIII of FGFR2. The known mutations involve five distinc t structural elements of the receptor. The changes within these elemen ts affect receptor function by various mechanisms, including altered d imerization, truncation, increased mobility between Ig domains, disint egration of IgIII, and alteration of the ligand-binding site.