Craniosynostosis, an abnormality of skull development in which the sutures of the growing calvarial bones fuse prematurely, occurs with a frequency of approximately 1 in 2500 live births. Recently, six autosomal dominant craniosynostotic syndromes, Crouzon, Jackson-Weiss, Pfeiffer, Apert, Crouzon with acanthosis nigricans and Beare-Stevenson cutis gyra were shown to be associated with mutations in either fibroblast growth factor receptor (FGFR)-l, FGFR-2 or FGFR-3. In addition, several dwarfing syndromes, achondroplasia, thanatophoric dysplasia types I and II, and hypochondroplasia were shown to be associated with mutations in FGFR-3. The FGFRs consist of a family of four high affinity transmembrane tyrosine kinase receptors. The prototype FGFR is comprised of an extracellular ligand-binding domain made up of three immunoglobulin (Ig)-like domains, a hydrophobic membrane-spanning region and a cytoplasmic tyrosine kinase domain. Mutations in the extracellular ligand-binding domain and the transmembrane domain of FGFR-1, FGFR-2 and FGFR-3 have been associated with craniosynostotic syndromes while mutations in the extracellular, transmembrane and tyrosine kinase domains of FGFR-3 have been associated with dwarfing syndromes. Our recent studies indicate that mutations in the extracellular, transmembrane and tyrosine kinase domains that are associated with craniosynostosis and other skeletal dysplasias result in ligand-independent constitutive activation of the mutant receptors. The central hypothesis of this application is that point mutations in FGFRs that are associated with craniosynostosis and other skeletal dysplasias result in constitutive activation of these receptors and that these receptors have altered signal transduction capabilities compared to their wild-type counterparts. This altered signaling capacity may in part be responsible for the phenotypic manifestations of these mutations. Accordingly, the specific aims of the proposal are: 1) to determine whether additional mutations identified in FGFRs that are associated with skeletal dysplasias result in constitutive receptor activation; 2) to determine whether these different mutations impart the mutant receptors with altered signal transduction properties, and 3) to determine whether constitutively activating mutations in FGFRs result in altered stability or intracellular trafficking. Together, these studies should begin to elucidate the role of mutant FGFRs in the pathogenesis of craniosynostotic conditions, as well as the role of FGFRs in normal bone growth and development.
