A Pro253Arg mutation in fibroblast growth factor receptor 2 (Fgfr2) causes skeleton malformation mimicking human Apert syndrome by affecting both chondrogenesis and osteogenesis
A Pro253Arg mutation in fibroblast growth factor receptor 2 (Fgfr2) causes skeleton malformation mimicking human Apert syndrome by affecting both chondrogenesis and osteogenesis
复制标题
成纤维细胞生长因子受体 2 (Fgfr2) 中的 Pro253Arg 突变通过影响软骨形成和成骨而导致类似于人类阿佩尔综合征的骨骼畸形
DOI：
10.1016/j.bone.2007.11.019
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发表时间：
2008-04-01
期刊：
影响因子：
4.1
通讯作者：
Chen, Lin
中科院分区：
文献类型：
--
作者：
Yin, Liangjun;Du, Xiaolan;Chen, Lin
Apert 综合征是最严重的颅缝早闭之一，主要由成纤维细胞生长因子受体 2 (FGFR2) 的 Ser252Trp(S252W) 或 Pro253Arg(P253R) 突变引起。 Apert综合征是一种常染色体显性遗传疾病，主要表现为颅面缝线过早融合导致的颅骨畸形以及并指畸形等。近三分之一的Apert综合征病例是由FGFR2的P253R突变引起的。 FGFR2 P253R 突变导致的 Apert 综合征的发病机制尚不完全清楚。在这里，我们报道了 Fgfr2 携带 P253R 突变的敲入小鼠模型。突变小鼠表现出较小的体型和短头畸形。对突变头骨和长骨的分析显示，冠状缝过早融合，颅底和长骨生长板缩短。体外器官培养研究进一步表明，与野生型同窝小鼠相比，突变小鼠的冠状缝过早融合，长骨生长迟缓。用 Erk1/2 抑制剂 PD98059 处理培养的颅骨和股骨，分别部分缓解冠状缝融合和股骨生长迟缓。我们的数据表明，Fgfr2 中的 P253R 突变直接影响膜内和软骨内骨化，导致冠状缝过早闭合以及长骨和颅底生长迟缓。 Erk1/2信号通路部分介导了Fgfr2 P253R突变对颅缝和长骨的影响。 (c) 2007 Elsevier Inc. 保留所有权利。
Apert syndrome is one of the most severe craniosynostosis that is mainly caused by either a Ser252Trp(S252W) or Pro253Arg(P253R) mutation in fibroblast growth factor receptor 2 (FGFR2). As an autosomal dominant disorder, Apert syndrome is mainly characterized by skull malformation resulting from premature fusion of craniofacial sutures, as well as syndactyly, etc. A P253R mutation of FGFR2 results in nearly one-thirds of the cases of Apert syndrome. The pathogenesis of Apert syndrome resulting from P253R mutation of FGFR2 is still not fully understood. Here we reported a knock-in mouse model carrying P253R mutation in Fgfr2. The mutant mice exhibit smaller body size and brachycephaly. Analysis of the mutant skulls and long bones revealed premature fusion of coronal suture, shortened cranial base and growth plates of long bones. In vitro organ culture studies further revealed that, compared with wild-type littermates, the mutant mice have prematurely fused coronal sutures and retarded long bone growth. Treatment of the cultured calvaria and femur with PD98059, an Erk1/2 inhibitor, resulted in partially alleviated coronal suture fusion and growth retardation of femur respectively. Our data indicated that the P253R mutation in Fgfr2 directly affect intramembranous and endochondral ossification, which resulted in the premature closure of coronal sutures and growth retardation of long bones and cranial base. And the Erk1/2 signaling pathway partially mediated the effects of P253R mutation of Fgfr2 on cranial sutures and long bones. (c) 2007 Elsevier Inc. All rights reserved.