1998
DOI: 10.1093/hmg/7.9.1475
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Apert syndrome mutations in fibroblast growth factor receptor 2 exhibit increased affinity for FGF ligand

Abstract: Dominantly acting mutations of the fibroblast growth factor (FGF) receptor 2 (FGFR2) gene have been implicated in various craniosynostosis syndromes. Apert syndrome, characterized in addition by syndactyly of the limbs, involves specific mutations at two adjacent residues, Ser252Trp and Pro253Arg, predicted to lie in the linker region between IgII and IgIII of the FGFR2 ligand-binding domain. We have analysed the interaction of FGF ligands with wild-type and Apert-type mutant FGFR2 ectodomains in solution. Wil… Show more

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Cited by 234 publications
(157 citation statements)
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“…Recently, in vitro analysis of the most common Apert mutations (FGF-R2 mutations; Ser252Trp and Pro253Arg) demonstrated increased affinity for FGF-2 ligand as compared to wildtype FGF-R2. 6 Our findings demonstrate that AdCAFGF-TR infection of the dural tissues underlying the PF cranial suture inhibited physiological cranial suture fusion, whereas AdCAsFGF-2 infection of the dural tissues underlying the COR suture resulted in fusion of this normally patent suture. In addition, we show that alterations in FGF biological activity is associated with significant changes in cellular proliferation and TGF-␤1 expression by NRCs and PFDCs.…”
Section: Discussionmentioning
confidence: 57%
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“…Recently, in vitro analysis of the most common Apert mutations (FGF-R2 mutations; Ser252Trp and Pro253Arg) demonstrated increased affinity for FGF-2 ligand as compared to wildtype FGF-R2. 6 Our findings demonstrate that AdCAFGF-TR infection of the dural tissues underlying the PF cranial suture inhibited physiological cranial suture fusion, whereas AdCAsFGF-2 infection of the dural tissues underlying the COR suture resulted in fusion of this normally patent suture. In addition, we show that alterations in FGF biological activity is associated with significant changes in cellular proliferation and TGF-␤1 expression by NRCs and PFDCs.…”
Section: Discussionmentioning
confidence: 57%
“…The gain-of-function associated with the mutated FGF-Rs has been attributed to ligand-independent dimerization/activation, and more recently to increased affinity of the mutated FGF-Rs for ligand, specifically FGF-2. [2][3][4][5][6] The mechanism for ligand-independent FGF-R dimerization and subsequent activation has been attributed to disruption of intramolecular disulfide bonds in the third immu- noglobulin loop of the FGF-R as a result of a point mutation and loss of an IgIII-associated cysteine residue. [2][3][4][5] Similarly, Robertson and colleagues 36 demonstrated that FGF-R mutations not involving cysteine substitutions may disrupt intramolecular disulfide bonds by altering the conformation of the IgIII domain.…”
Section: Discussionmentioning
confidence: 99%
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“…46 The discrepancy between this mouse model and the human situation might be related to differences in the developmental stages (human adult versus mouse embryo) and/or homozygosity of mutant animals versus heterozygosity of human mutations. Since FGFR2 mutations causing Apert syndrome and some cases of PS alter FGF binding specificity or result in ectopic FGFR2 IIIb expression, 38,39,43 we speculate that in our case, inappropriate expression of the IIIb isoform in mesenchymal cells would allow binding and signalling through FGF10 or FGF7 ligands, leading to a gain-of-function mechanism. If we assume that limb anomalies in JW variants, PS and AS require threshold signalling to become detectable, it would mean that the level of expression of the IIIb isoform in mesenchymal cells of our patient was lower than in previously reported Pfeiffer patients, 43,44 and that lower limbs are more sensitive to illegitimate activation than upper limbs.…”
Section: Discussionmentioning
confidence: 84%
“…So far, FGFR2 mutations causing craniosynostoses proved to be gain-of-function mutations resulting in either ligandindependent activation of the receptor 37 or enhancing the affinity of ligand binding 38 or producing illegitimate ligand binding and signalling. 39,40 Consequently, the identification of a 2 bp deletion in a familial form of JW variant causing the appearance of a putative premature termination codon was somewhat unexpected.…”
Section: Discussionmentioning
confidence: 99%