APERT SYNDROME RESULTS FROM LOCALIZED MUTATIONS OF FGFR2 AND IS ALLELIC WITH CROUZON SYNDROME

Apert syndrome is a distinctive human malformation comprising craniosy nostosis and severe syndactyly of the hands and feet. We have identifi ed specific missense substitutions involving adjacent amino acids (Ser 252Trp and Pro253Arg) in the linker between the second and third extra cellular immunoglobulin (Ig) domains of fibroblast growth factor recep tor 2 (FGFR2) in all 40 unrelated cases of Apert syndrome studied. Cro uzon syndrome, characterized by craniosynostosis but normal limbs, was previously shown to result from allelic mutations of the third Ig dom ain of FGFR2. The contrasting effects of these mutations provide a gen etic resource for dissecting the complex effects of signal transductio n through FGFRs in cranial and limb morphogenesis.