Craniosynostosis is characterized by premature fusion of calvarial bones, resulting in abnormal head shape. It is one of the most frequent human malformations, occurring either as an isolated abnormality or in association with other congenital anomalies. Saethre-Chotzen syndrome is a common craniosynostosis condition with autosomal dominant inheritance, high penetrance, and variable expressivity. Forty-six percent of these patients have mutations in the TWIST gene. This gene codes for a putative transcription factor with a basic helix-loop-helix motif, suggesting that it must dimerize prior to binding its DNA target. Another 22% of patients have fibroblast Growth Factor Receptor (FGFR) mutations. In Drosophila, twist is an upstream regulator of DFR1, a homologue of FGFR. These data suggest that TWIST and FGFR may be components of a conserved, molecular pathway implicated in cranial development. Mutation of other genes involved in this pathway may also cause craniosynostosis. The goal of this proposal is to study the molecular pathogenesis of craniosynostosis, and in particular, Saethre-Chotzen syndrome.
The specific aims are to: 1) identify mutations in the other 32% of Saethre-Chotzen syndrom patients by screening candidate genes presumed to be involved in the same molecular pathway (e.g., FRS2, SNAIL); 2) identify mutations in candidate genes (e.g., BARX2) for other non-syndromic and syndromic craniosynostosis conditions, such as metopic synostosis; 3) determine the mechanism(s) of the haploinsufficiency of TWIST mutations in Saethre-Chotzen syndrome patients by assaying for reduction of TWIST transcription of protein levels, dimerization, or DNA binding; 4) determine in Saethre-Chotzen syndrome patients, the effect of TWIST mutations on the level of expression of other candidate genes of the molecular pathway. Those affected would be downstream of TWIST, while those not affected may be upstream components; and 5) determine the gene mutated in a rabbit model of coronal synostosis which may proven to be a useful system to further delineate the molecular pathway of craniosynostosis which may prove to be a useful system to further delineate the molecular pathway of craniosynostosis. These studies may identify additional craniosynostosis loci and provide insight into the molecular pathways involved in development of the skull.
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