Pulleyn, Louise Joan; (1998) The genetics of craniosynostosis. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Craniosynostosis, the premature fusion of the cranial sutures, is a common disorder resulting in craniofacial malformations. It occurs in syndromes, which are distinguishable by other dysmorphic features. Causative mutations have been found in three members of the Fibroblast Growth Factor Receptor family (FGFR1, -2 and -3), with the majority of the mutations occurring within the Immunoglobulin-like loop HI (IgIII) of FGFR2. Over 50% of cases do not have an identified causative mutation in this region. By screening the extracellular domain of FGFR2 a number of novel and recurrent mutations were identified in both syndromic and non-syndromic cases, broadening the sites and the range of phenotypes associated with FGFR2 mutations. Mutations at an acceptor splice site were shown to cause exon skipping, which would result in premature termination of the protein. This is currently uncharacteristic of the FGFR mutations. A conserved serine-proline dipeptide in the IgII-III linker region of the FGFR molecules, which is a site of mutations in FGFR1, -2 and -3 in a variety of phenotypes was screened for changes in all four FGFRs in a large sample set. No mutations or polymorphisms were revealed, emphasizing the specificity of the mutations at the site. At other sites in IgIII, different syndromic phenotypes can arise from identical mutations in FGFR2. These samples were tested for an association between the phenotype and a polymorphic variant in relevant genes. To identify additional genes involved in craniosynostosis, candidate genes were analysed in non-syndromic families, and also in families with craniofrontonasal dysplasia (CFND). Two CFND families were shown to be consistent with linkage to Xp22, although in one family this included an apparently unaffected male with a normal clinical phenotype sharing the affected marker allele haplotype, emphasizing the variability of the male phenotype in the condition.

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