fibroblast growth factor receptor (FGFR) -related craniosynostosis syndromes are caused by many different mutations within FGFR-1, 2, 3, and certain FGFR mutations are associated with more than one clinical syndrome.
Here we investigate growth of the skull in two inbred mouse models each carrying one of two gain-of-function mutations in FGFR2 on neighboring amino acids (S252W and P253R) that in humans cause Apert syndrome, one of the most severe FGFR-related craniosynostosis syndromes.
We provide experimental evidence that these mutations affect normal FGFR2 splicing and document the clinical consequences, which include a mild Crouzon syndrome phenotype and reduced penetrance of craniosynostosis.
Besides the cranial phenotype, brain dysmorphologies are present and are not seen in other FGFR2-asociated craniosynostosis, such as Crouzon syndrome (CS).
Several of the defects observed in the Fgfr2 (W290R) homozygous mouse mutant are attributable to a loss-of-function mechanism in contrast to the frequently reported gain-of-function receptor function associated with mutated FGF receptors in craniosynostosis.
Fgfr2+/Y394C mice exhibited epidermal hyperplasia and premature closure of cranial sutures (craniosynostosis) due to abnormal cell proliferation and differentiation.
Patients with Apert syndrome (craniosynostosis syndrome due to mutations in FGFR2) are most severely affected in terms of intellectual disability, developmental delay, central nervous system anomalies, and limb anomalies.
Perhaps increased FGFR2 activation during this embryonic period leads to abnormal differentiation or regression of the tail bud and, in turn, sacrococcygeal eversion, in certain patients with severe syndromic craniosynostosis.
Gain-of-function mutations in FGFR2 cause Apert syndrome (AS), a disease characterized by craniosynostosis and limb bone defects both due to abnormalities in bone differentiation and remodeling.
In 1996, two mutations in the fibroblast growth factor receptor 2 gene were found to cause this syndrome, thereby including BSS in the fibroblast growth factor receptor gene-related craniosynostosis spectrum.
Apert syndrome is 1 of the 5 craniosynostosis syndromes that shore clinical features and are caused by allelic mutations in the fibroblast growth factor receptor 2 (FGFR2) gene.
The majority of the mutations identified are identical to germline mutations in FGFR2 and FGFR3 that cause craniosynostosis and hypochondroplasia syndromes and result in both ligand-independent and ligand-dependent receptor activation.
Apert syndrome is one of the most severe craniosynostosis that is mainly caused by either a Ser252Trp(S252W) or Pro253Arg(P253R) mutation in fibroblast growth factor receptor 2 (FGFR2).
Syndromic craniosynostoses (Saethre-Chotzen, Pfeiffer 1, 2, 3, Apert, Crouzon, mainly) are particular in this that a single gene defect (mostly fibroblast growth factor receptor [FGFR] 2) generates different clinical phenotypes that characterize these syndromes.