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Investigating the molecular pathogenesis of craniosynostosis:
Craniosynostosis is a debilitating clinical condition characterized by the premature fusion of cranial sutures. The prevalence of craniosynostosis is high, at approximately 1 in 2500 live births, and treatment is currently limited to surgery, genetic counseling, orthodontics and social support. Craniosynostosis can occur sporadically, or as part of one of several known genetic syndromes. Greater understanding of the molecular pathogenesis of craniosynostosis will aid in the development of interceptive or adjunctive biologic treatments for patients with this medically and socially challenging condition.
Phosphate homeostasis and craniosynostosis:
Because the more common forms of syndromic craniosynostosis are associated with mutations in fibroblast growth factor receptors (FGFR’s), we are interested in understanding the role of FGF signaling in bone mineralization and craniofacial skeletal development. Our current effort is focused on establishing the role of pyrophosphate and phosphate metabolism in the development of syndromic craniosynostosis using the FGFR2-C342Y mouse model of Crouzon syndrome. We are currently working towards understanding the developmental function of pre-osteoblastic PC-1, and establishing the relative contribution of hypophosphatemia and hyperpyrophosphatemia in the overall effects of FGF’s on osteoblast differentiation, bone mineralization and craniosynostosis.
Biochemical effects of craniosynostosis syndrome associated mutations in fibroblast growth factor receptor-2 (FGFR2):
In an effort to better understand the biochemical consequences of craniosynostosis associated mutations on FGF receptor function, we are investigating the effect of the Crouzon C278F mutation on FGFR2 expression, trafficking and signaling. We find that Crouzon mutant FGFR2 exhibits increased degradation and limited cellular sub-localization in calvarial pre-osteoblastic cells, and that this is likely the result of incomplete receptor glycosylation. Glycosylation deficient wild type FGFR2 and FGFR2-C278F are active in the absence of ligand and restricted to ER and Golgi subcellular compartments. Our results raise new questions concerning the mechanism by which FGFR2 mutations influence craniosynostosis. Our findings indicate that, depending on cell type, auto-activating mutations in FGFR2 might influence craniofacial development by causing enhanced FGFR2 signaling, by causing FGFR2 signaling from an inappropriate subcellular compartment (ER and Golgi versus cell surface and endosomal membranes), or by enhancing FGFR2 degradation to such an extent that total FGFR2 signaling is diminished. To determine which of these mechanisms pertains to craniosynostosis, we are currently working towards the development of methods to address the extent and subcellular locus of FGFR2 activation in situ.