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

被引:17
作者
Britto, JA
Moore, RL
Evans, RD
Hayward, RD
Jones, BM
机构
[1] Guys Hosp, Guys Kings & St Thomas Dent Inst, Dept Orthopaed & Paediat Dent, London SE1 9RT, England
[2] Inst Child Hlth, Dev Biol Unit, London, England
[3] Great Ormond St Hosp Children, Craniofacial Ctr, London WC1N 3JH, England
关键词
fibroblast growth factor receptor; craniosynostosis; Apert syndrome; Pfeiffer syndrome;
D O I
10.3171/jns.2001.95.4.0660
中图分类号
R74 [神经病学与精神病学];
学科分类号
摘要
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.
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收藏
页码:660 / 673
页数:14
相关论文
共 64 条
[1]   SUTURE PATHOLOGY IN CRANIOSYNOSTOSIS [J].
ALBRIGHT, AL ;
BYRD, RP .
JOURNAL OF NEUROSURGERY, 1981, 54 (03) :384-387
[2]   Apert syndrome mutations in fibroblast growth factor receptor 2 exhibit increased affinity for FGF ligand [J].
Anderson, J ;
Burns, HD ;
Enriquez-Harris, P ;
Wilkie, AOM ;
Heath, JK .
HUMAN MOLECULAR GENETICS, 1998, 7 (09) :1475-1483
[3]  
Apert E., 1906, B SOC MED PARIS, V23, P1310
[4]   Fibroblast growth factor receptors: lessons from the genes [J].
Burke, D ;
Wilkes, D ;
Blundell, TL ;
Malcolm, S .
TRENDS IN BIOCHEMICAL SCIENCES, 1998, 23 (02) :59-62
[5]  
Carlton MBL, 1998, DEV DYNAM, V212, P242, DOI 10.1002/(SICI)1097-0177(199806)212:2<242::AID-AJA8>3.3.CO
[6]  
2-Z
[7]   Pleiotropic features of syndromic craniosynostoses correlate with differential expression of fibroblast growth factor receptors 1 and 2 during human craniofacial development [J].
Chan, CTJ ;
Thorogood, P .
PEDIATRIC RESEARCH, 1999, 45 (01) :46-53
[8]  
Chun K, 1998, AM J MED GENET, V77, P219, DOI 10.1002/(SICI)1096-8628(19980518)77:3<219::AID-AJMG6>3.0.CO
[9]  
2-K
[10]   CHRONIC TONSILLAR HERNIATION IN CROUZONS AND APERTS SYNDROMES - THE ROLE OF PREMATURE SYNOSTOSIS OF THE LAMBDOID SUTURE [J].
CINALLI, G ;
RENIER, D ;
SEBAG, G ;
SAINTEROSE, C ;
ARNAUD, E ;
PIERREKAHN, A .
JOURNAL OF NEUROSURGERY, 1995, 83 (04) :575-582