Britto, Jonathan Anthony; (2001) Syndromic craniofacial dysostosis - From genotype to phenotype. Studies of FGFR gene expression in human craniofacial development and craniosynostosis. Doctoral thesis (M.D), UCL (University College London).

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Abstract

Fibroblast growth factor receptors (FGFRs) are a subset of receptor tyrosine kinases. Receptor diversity results from the differential splicing of mRNA to generate membrane bound and secreted proteins. FGFRl, 2, and 3 signalling pathways appear fundamental to human skeletogenesis; as illustrated by a range of cranioskeletal and dwarfing dysplasias that occur as a result of activating FGFR mutations. These phenotypes include the syndromic craniofacial dysostoses, which are related human developmental disorders combining variable craniofacial anomaly with extracranial manifestations. Common to these syndromes is craniosynostosis, in which the fibrous cranial suture is prematurely replaced by bone. Mutations in FGFR3 additionally cause the dwarfing chondrodysplasias, which may also feature craniosynostosis and basicranial dysplasia. Analysis of the expression of FGFR 1-3, and the ligands FGF2, FGF4, and FGF7, has been undertaken in human craniofacial tissues representing early foetal, late foetal, and infant stages of development. All tissue was collected and studied within strict ethical guidelines. FGFR transcripts were detected using isoform specific probes in - situ hybridisation studies, whilst protein products were detected by immuno - histochemistry. FGFRl, 2, and 3 are differentially expressed throughout human cranioskeletal development and human craniosynostosis. In infant sagittal suture fusion, FGFRl is a marker of pre-osseous proliferative and early osseous differentiative stages, whereas the FGFR2 - Iglllc (BEK) isoform is a marker of later osseous differentiation. Differential expression of FGFR1-3 in human craniofacial development and infant craniosynostosis correlates with the clinical craniofacial dysmorphism of the related syndromes. Comparison of mutant FGFR2 - C278F and mFGFR2 - P253R human embryo-foetal cranial skeletogenesis to age - matched wild - type, suggests that FGFR2 functional gain results in negative - autoregulation of FGFR2 expression in- situ. Furthermore, the isoform - specific expression of FGFR2 and ligands in human palatogenesis predicts a dominant - negative role for FGFR2 - Igllla/b (KGFR) in the pathogenesis of Apert cleft palate.

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