Uncoupling Fibroblast Growth Factor receptor 2 ligand binding specificity leads to Apert syndrome-like phenotypes

Washington University in St. Louis, San Luis, Missouri, United States
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 04/2001; 98(7). DOI: 10.1073/pnas.081082498
Source: PubMed Central
Download full-text


Available from: David Ornitz, Jan 25, 2014
  • Source
    • "The first mutation, S252W, is more common, occurring in 67% of patients. Both mutations affect the highly conserved linker region between the immunoglobulin-like II and III domains, resulting in increased affinity and altered specificity of fibroblast growth factor (FGF) ligand binding [7]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: A S252W mutation of fibroblast growth factor receptor 2 (FGFR2), which is responsible for nearly two-thirds of Apert syndrome (AS) cases, causes retarded development of the skeleton and skull malformation resulting from premature fusion of the craniofacial sutures. We utilized a Fgfr2(+/S252W) mouse (a knock-in mouse model mimicking human AS) to demonstrate decreased bone mass due to reduced trabecular bone volume, reduced bone mineral density, and shortened growth plates in the long bones. In vitro bone mesenchymal stem cells (BMSCs) culture studies revealed that the mutant mice showed reduced BMSC proliferation, a reduction in chondrogenic differentiation, and reduced mineralization. Our results suggest that these phenomena are caused by up-regulation of p38 and Erk1/2 phosphorylation. Treatment of cultured mutant bone rudiments with SB203580 or PD98059 resulted in partial rescue of the bone growth retardation. The p38 signaling pathway especially was found to be responsible for the retarded long bone development. Our data indicate that the S252W mutation in FGFR2 directly affects endochondral ossification, resulting in growth retardation of the long bone. We also show that the p38 and Erk1/2 signaling pathways partially mediate the effects of the S252W mutation of FGFR2 on long bone development.
    Full-text · Article · Jan 2014 · PLoS ONE
  • Source
    • "It was shown experimentally that one of these rearrangements drove illegitimate expression of the FGFR2b splice form in fibroblasts, a mesenchymal derivative [16]. Hence the common factor linking exon IIIa missense mutations and exon IIIc rearrangements, both causing AS, appears to be the autocrine activation of signalling by FGF10 and/or related ligands in the mesenchyme [6,14-18]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Signalling by fibroblast growth factor receptor type 2 (FGFR2) normally involves a tissue-specific alternative splice choice between two exons (IIIb and IIIc), which generates two receptor isoforms (FGFR2b and FGFR2c respectively) with differing repertoires of FGF-binding specificity. Here we describe a unique chimeric IIIb/c exon in a patient with Apert syndrome, generated by a non-allelic homologous recombination event. We present a child with Apert syndrome in whom routine genetic testing had excluded the FGFR2 missense mutations commonly associated with this disorder. The patient was found to harbour a heterozygous 1372 bp deletion between FGFR2 exons IIIb and IIIc, apparently originating from recombination between 13 bp of identical DNA sequence present in both exons. The rearrangement was not present in the unaffected parents. Based on the known pathogenesis of Apert syndrome, the chimeric FGFR2 protein is predicted to act in a dominant gain-of-function manner. This is likely to result from its expression in mesenchymal tissues, where retention of most of the residues essential for FGFR2b binding activity would result in autocrine activation. This report adds to the repertoire of rare cases of Apert syndrome for which a pathogenesis based on atypical FGFR2 rearrangements can be demonstrated.
    Full-text · Article · Sep 2011 · BMC Medical Genetics
  • Source
    • "Mutations that affect the growth of long bones resulting in syndromes such as Achondroplasia (Ach) and Thanatophoric dysplasia (TD) are mainly localized to FGFR3. These autosomal dominant disorders are believed to reflect either an enhancement of receptor activity or a neomorphic gain-of-function effect [9-11]. During long bone development, FGF receptors are expressed in the epiphyseal growth plates: FGFR3 is expressed in the proliferating chondrocytes; FGFR1 is expressed in the hypertrophic chondrocytes; FGFR1 and FGFR2 are expressed in the perichondrium [4,12]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The flat bones of the skull (i.e., the frontal and parietal bones) normally form through intramembranous ossification. At these sites cranial mesenchymal cells directly differentiate into osteoblasts without the formation of a cartilage intermediate. This type of ossification is distinct from endochondral ossification, a process that involves initial formation of cartilage and later replacement by bone. We have analyzed a line of transgenic mice that expresses FGF9, a member of the fibroblast growth factor family (FGF), in cranial mesenchymal cells. The parietal bones in these mice show a switch from intramembranous to endochondral ossification. Cranial cartilage precursors are induced to proliferate, then hypertrophy and are later replaced by bone. These changes are accompanied by upregulation of Sox9, Ihh, Col2a1, Col10a1 and downregulation of CbfaI and Osteocalcin. Fate mapping studies show that the cranial mesenchymal cells in the parietal region that show a switch in cell fate are likely to be derived from the mesoderm. These results demonstrate that FGF9 expression is sufficient to convert the differentiation program of (at least a subset of) mesoderm-derived cranial mesenchyme cells from intramembranous to endochondral ossification.
    Full-text · Article · Feb 2006 · BMC Developmental Biology
Show more