A Pro253Arg mutation in fibroblast growth factor receptor 2 (Fgfr2) causes skeleton malformation mimicking human Apert syndrome by affecting both chondrogenesis and osteogenesis

Bone ◽  
2008 ◽  
Vol 42 (4) ◽  
pp. 631-643 ◽  
Author(s):  
Liangjun Yin ◽  
Xiaolan Du ◽  
Cuiling Li ◽  
Xiaoling Xu ◽  
Zhi Chen ◽  
...  
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Fibroblast Growth Factor Receptor ◽  
Growth Factor Receptor ◽  
Apert Syndrome ◽  
Fibroblast Growth

Negative autoregulation of fibroblast growth factor receptor 2 expression characterizing cranial development in cases of Apert (P253R mutation) and Pfeiffer (C278F mutation) syndromes and suggesting a basis for differences in their cranial phenotypes

2001 ◽  
Vol 95 (4) ◽  
pp. 660-673 ◽  
Author(s):  
Jonathan A. Britto ◽  
Rachel L. Moore ◽  
Robert D. Evans ◽  
Richard D. Hayward ◽  
Barry M. Jones
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Fibroblast Growth Factor Receptor ◽  
Growth Factor Receptor ◽  
Apert Syndrome ◽  
Fibroblast Growth ◽  
Content Type ◽  
Pfeiffer Syndrome ◽  
Negative Autoregulation ◽  
Fine Print

Object. Heterogeneous mutations in the fibroblast growth factor receptor 2 gene (FGFR2) cause a range of craniosynostosis syndromes. The specificity of the Apert syndrome—affected cranial phenotype reflects its narrow mutational range: 98% of cases of Apert syndrome result from an Ser252Trp or Pro253Arg mutation in the immunoglobulin-like (Ig)IIIa extracellular subdomain of FGFR2. In contrast, a broad range of mutations throughout the extracellular domain of FGFR2 causes the overlapping cranial phenotypes of Pfeiffer and Crouzon syndromes and related craniofacial dysostoses. Methods. In this paper the expression of FGFR1, the IgIIIa/c and IgIIIa/b isoforms of FGFR2, and FGFR3 is investigated in Apert syndrome (P253R mutation)— and Pfeiffer syndrome (C278F mutation)—affected fetal cranial tissue and is contrasted with healthy human control tissues. Both FGFR1 and FGFR3 are normally expressed in the differentiated osteoblasts of the periosteum and osteoid, in domains overlapped by that of FGFR2, which widely include preosseous cranial mesenchyme. Expression of FGFR2, however, is restricted to domains of advanced osseous differentiation in both Apert syndrome— and Pfeiffer syndrome—affected cranial skeletogenesis in the presence of fibroblast growth factor (FGF)2, but not in the presence of FGF4 or FGF7. Whereas expression of the FGFR2-IgIIIa/b (KGFR) isoform is restricted in normal human cranial osteogenesis, there is preliminary evidence that KGFR is ectopically expressed in Pfeiffer syndrome—affected cranial osteogenesis. Conclusions. Contraction of the FGFR2-IgIIIa/c (BEK) expression domain in cases of Apert syndrome— and Pfeiffer syndrome—affected fetal cranial ossification suggests that the mutant activation of this receptor, by ligand-dependent or ligand-independent means, results in negative autoregulation. This phenomenon, resulting from different mechanisms in the two syndromes, offers a model by which to explain differences in their cranial phenotypes.

scholarly journals Structural basis for fibroblast growth factor receptor 2 activation in Apert syndrome

2001 ◽  
Vol 98 (13) ◽  
pp. 7182-7187 ◽  
Author(s):  
O. A. Ibrahimi ◽  
A. V. Eliseenkova ◽  
A. N. Plotnikov ◽  
K. Yu ◽  
D. M. Ornitz ◽  
...  
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Fibroblast Growth Factor Receptor ◽  
Growth Factor Receptor ◽  
Apert Syndrome ◽  
Structural Basis ◽  
Fibroblast Growth

scholarly journals A Soluble Form of Fibroblast Growth Factor Receptor 2 (FGFR2) with S252W Mutation Acts as an Efficient Inhibitor for the Enhanced Osteoblastic Differentiation Caused by FGFR2 Activation in Apert Syndrome

2004 ◽  
Vol 279 (44) ◽  
pp. 45926-45934 ◽  
Author(s):  
Yukiho Tanimoto ◽  
Masahiko Yokozeki ◽  
Kenji Hiura ◽  
Kazuya Matsumoto ◽  
Hideki Nakanishi ◽  
...  
Keyword(s):  
Growth Factor ◽  
Mrna Expression ◽  
Fibroblast Growth Factor ◽  
Fibroblast Growth Factor Receptor ◽  
Growth Factor Receptor ◽  
Osteoblastic Differentiation ◽  
Apert Syndrome ◽  
Osteoblastic Cells ◽  
Nodule Formation ◽  
Fibroblast Growth

Apert syndrome is an autosomal dominant disease characterized by craniosynostosis and bony syndactyly associated with point mutations (S252W and P253R) in the fibroblast growth factor receptor (FGFR) 2 that cause FGFR2 activation. Here we investigated the role of the S252W mutation of FGFR2 on osteoblastic differentiation. Osteoblastic cells derived from digital bone in two Apert patients with the S252W mutation showed more prominent alkaline phosphatase activity, osteocalcin and osteopontin mRNA expression, and mineralized nodule formation compared with the control osteoblastic cells derived from two independent non-syndromic polydactyly patients. Stable clones of the human MG63 osteosarcoma cells (MG63-Ap and MG63-IIIc) overexpressing a splice variant form of FGFR2 with or without the S252W mutation (FGFR2IIIcS252W and FGFR2IIIc) showed a higher RUNX2 mRNA expression than parental MG63 cells. Furthermore MG63-Ap exhibited a higher osteopontin mRNA expression than did MG63-IIIc. The enhanced osteoblastic marker gene expression and mineralized nodule formation of the MG63-Ap was inhibited by the conditioned medium from the COS-1 cells overexpressing the soluble FGFR2IIIcS252W. Furthermore the FGF2-induced osteogenic response in the mouse calvarial organ culture system was blocked by the soluble FGFR2IIIcS252W. These results show that the S252W mutation in the FGFR2 gene enhances the osteoblast phenotype in human osteoblasts and that a soluble FGFR2 with the S252W mutation controls osteoblast differentiation induced by the S252W mutation through a dominant negative effect on FGFR2 signaling in Apert syndrome.

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