Loss of fibroblast growth factor receptor 2 ligand-binding specificity in Apert syndrome
Loss of fibroblast growth factor receptor 2 ligand-binding specificity in Apert syndrome
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DOI：
10.1073/pnas.97.26.14536
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发表时间：
2000-12-19
影响因子：
11.1
通讯作者：
Ornitz, DM
中科院分区：
文献类型：
--
作者：
Yu, K;Herr, AB;Ornitz, DM
颅缝早闭综合征是由成纤维细胞生长因子受体基因（Fgfrs）的各种突变引起的常染色体显性人类骨骼疾病。Apert综合征（AS）是最严重的颅缝早闭综合征之一，与严重的手足并指畸形和中枢神经系统畸形有关。AS是由连接FGFR 2 Ig样结构域II和III的高度保守区域中两个相邻氨基酸残基之一（S252W或P253R）的特异性错义突变引起的。在这里，我们证明，这些突变打破了一个重要的规则，配体特异性的FGFR2。我们发现S252W突变允许间充质剪接形式的FGFR2（FGFR2c）结合并被间充质表达的配体FGF7或FGF10激活，并且允许上皮剪接形式的FGFR2（FGFR2b）被FGF2、FGF6和FGF9激活。这些数据表明FGFR 2的配体特异性丧失，受体活化保留配体依赖性。这些数据表明AS的严重表型可能是由FGFR2的异位配体依赖性激活引起的。
Craniosynostosis syndromes are autosomal dominant human skeletal diseases that result from various mutations in fibroblast growth factor receptor genes (Fgfrs). Apert syndrome (AS) is one of the most severe craniosynostosis syndromes and is associated with severe syndactyly of the hands and feet and with central nervous system malformations. AS is caused by specific missense mutations in one of two adjacent amino acid residues (S252W or P253R) in the highly conserved region linking Ig-like domains II and III of FGFR2. Here we demonstrate that these mutations break one of the cardinal rules governing ligand specificity of FGFR2. We show that the S252W mutation allows the mesenchymal splice form of FGFR2 (FGFR2c) to bind and to be activated by the mesenchymally expressed ligands FGF7 or FGF10 and the epithelial splice form of FGFR2 (FGFR2b) to be activated by FGF2, FGF6, and FGF9. These data demonstrate loss of ligand specificity of FGFR2 with retained ligand dependence for receptor activation. These data suggest that the severe phenotypes of AS likely result from ectopic ligand-dependent activation of FGFR2.