FGF18, a high affinity ligand for FGFR3, is the only FGF-based drug currently in clinical trials for osteoarthritis. Of the four FGF receptors (FGFRs 1–4), FGFR1 and FGFR3 are strongly implicated in osteoarthritis, and FGFR1 antagonists, as well as agonists of FGFR3, have shown therapeutic efficacy in mouse models of spontaneous and surgically induced osteoarthritis.
Regulated fibroblast growth factor (FGF) signalling is a prerequisite for the correct development and homeostasis of articular cartilage, as evidenced by the fact that aberrant FGF signalling contributes to the maldevelopment of joints and to the onset and progression of osteoarthritis. Although the implementation of a stepwise screening strategy is useful in diagnostics, mutations in unscreened regions of genes associated with craniosynostosis may explain a small proportion of craniosynostosis cases. The identification of a mutation in these clinically heterogeneous disorders can aid recurrence risk assessments. The mutation is predicted to alter the protein tertiary structure which may impair its binding to its ligand, FGF1. Alanine 334 is evolutionarily conserved in vertebrates and is located at the amino terminus of the βF loop in the FGFR3c isoform. The mutation segregated with mild craniosynostosis in the family and was absent in 188 normal controls. Here, we report a novel mutation in exon 8 (IIIc) of FGFR3, p.Ala334Thr, in a young boy with mild craniosynostosis. Other FGFR3 mutations result in various skeletal dysplasias: achondroplasia, hypochondroplasia, and thanatophoric dysplasia.
The associated of FGFR3 mutations with craniosynostosis has been restricted to three mutations, the common p.Pro250Arg in Muenke syndrome, p.Ala391Glu in Crouzon syndrome with acanthosis nigricans, and p.Pro250Leu identified in a family with isolated craniosynostosis. Mutations in FGFR1, FGFR2, or FGFR3, among others, are often responsible for these syndromic cases. Craniosynostosis is the premature fusion of one or more sutures of the skull, which can be syndromic or isolated.
0 kommentar(er)
