Abstract
Craniosynostosis syndromes are developmental disorders that cause an abnormal shape of the skull due to the premature fusion of cranial sutures. Enormous progress has been made recently in understanding the genetic background of these disorders and a classification of syndromes on a genetic basis is beginning to emerge. Members of at least three gene families that play an important role in vertebrate development are associated with different craniosynostosis syndromes. Here we review the genetic aspects of this fast-moving field.
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Acknowledgements
We would like to thank Dr. J.M. Vaandrager for critically reading the manuscript, and Prof. Dr. Galjaard for his continuous support.
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FGFs and Their Receptors
FGFs and Their Receptors
FGFs constitute a family of related signalling molecules that act to promote the growth and differentiation of cells of different origins. In mammals, nine members of the FGF family have been described so far [33]. FGFs act by binding and activating specific cell surface receptors, which comprise a family of related but individually distinct tyrosine kinase receptors [34–36]. These FGFRs each possess a similar protein structure with three immunoglobulin (Ig)-like domains in the extracellular region, a single membrane-spanning segment and a cytoplasmic tyrosine kinase domain split by a kinase insert (fig. 1). Some cDNA clones have been identified encoding only the second and third Ig domains, which are still functional as a FGFR. Four FGFR genes have been found so far in humans and the diversity of these receptors is further increased by differential RNA splicing [37–41]. Alternative exon usage in the second half of the third Ig loop results in different ligand-binding properties. Ligand-induced receptor activation is mediated by receptor oligomerization via conformation alteration of the extracellular domain. This oligomerization is proposed to stabilize interactons between adjacent cytoplasmatic regions and leads to activation of the kinase function [37, 38, 41].
For FGFR1 and FGFR2, alternative splice products have been characterized, and apart from the FGFR form of the genes, a keratinocyte growth factor receptor (KGFR)-like product is found. The two isoforms are identical except for a 49-amino-acid sequence spanning the second half of the third Ig loop in the extracellular region. Control of these alternative splice variants appears to involve trans-acting factors. The variation in the expressed gene product is highly significant since there is a distinction in the ligandbinding characteristics of the two isoforms leading to functional differences.
The expression pattern of the kgfr and fgfr isoforms of Fgfr1 and Fgfr2 has been studied in developing mouse embryos with exon-specific probes [38, 42]. Both forms are expressed as early as gastrulation but show a distinctive expression pattern, with exclusive alternative splicing in different cell types. The kgfr isoform plays a role in skin development, the fgfr form is preferentially expressed in osteogenesis. This expression pattern is consistent with a role of the fgfr isoforms in craniofacial development.
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Heutink, P., Vermeij-Keers, C. & Oostra, B.A. The Genetic Background of Craniosynostosis Syndromes. Eur J Hum Genet 3, 312–323 (1995). https://doi.org/10.1159/000472315
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DOI: https://doi.org/10.1159/000472315
