TI  - Loss of <prot>fibroblast growth factor receptor 2</prot> ligand-binding specificity in
      Apert syndrome.
PG  - 14536-41
AB  - Craniosynostosis syndromes are autosomal dominant human skeletal diseases
      that result from various mutations in fibroblast growth factor receptor
      genes (Fgfrs). Apert syndrome (AS) is one of the most severe
      craniosynostosis syndromes and is associated with severe syndactyly of the
      hands and feet and with central nervous system malformations. AS is caused
      by specific missense 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 <prot>FGFR2</prot>. Here we demonstrate that these mutations break one of
      the cardinal rules governing ligand specificity of <prot>FGFR2</prot>. We show that the
      S252W mutation allows the mesenchymal splice form of  <prot>FGFR2</prot> (<prot>FGFR2c</prot>)  to
      bind and to be activated by the mesenchymally expressed ligands <prot>FGF7</prot>  or
       <prot>FGF10</prot>  and the epithelial splice form of    <prot>FGFR2</prot> (<prot>FGFR2b</prot>)     to be activated by
       <prot>FGF2</prot> ,  <prot>FGF6</prot> , and <prot>FGF9</prot> . These data demonstrate loss of ligand specificity of
      <prot>FGFR2</prot> with retained ligand dependence for receptor activation. These data
      suggest that the severe phenotypes of AS likely result from ectopic
      ligand-dependent activation of <prot>FGFR2</prot>.
AD  - Departments of Molecular Biology and Pharmacology, and Biochemistry,
