A Ser250Trp substitution in mouse fibroblast growth factor receptor 2 (Fgfr2) results in craniosynostosis
A Ser250Trp substitution in mouse fibroblast growth factor receptor 2 (Fgfr2) results in craniosynostosis
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DOI：
10.1016/s8756-3282(03)00222-9
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发表时间：
2003-08-01
期刊：
影响因子：
4.1
通讯作者：
Deng, CX
中科院分区：
文献类型：
--
作者：
Chen, L;Li, D;Deng, CX
阿佩尔综合征（AS）是最严重的颅缝早闭之一，其特征是颅面缝线过早融合。成纤维细胞生长因子受体 2 (FGFR2) 中的 Ser252Trp 或 Pro253Arg 突变是几乎所有已知 AS 病例的原因。在这里，我们发现携带激活突变 Ser250Trp（对应于人类 FGFR2 中的 Ser252Trp）的突变小鼠具有模仿 AS 患者中发现的颅骨异常的畸形。突变小鼠 (Fgfr2(250/+)) 体型较小，患有短头畸形，头骨扭曲，眼睛间距较宽。出乎意料的是，冠状缝的过早闭合伴随着骨形成的减少而不是增加。我们证明Fgfr2-Ser250Trp突变不会引起细胞增殖和分化的明显改变；然而，它会导致突变冠状缝中 Bax 表达增加和成骨细胞凋亡。加速的细胞死亡可能会减少扁骨成骨前沿之间的空间，并导致这些骨头的物理接触。因此，我们的数据表明细胞凋亡失调在 AS 相关表型的发病机制中起着重要作用。 (C) 2003 Elsevier Inc. 保留所有权利。
Apert syndrome (AS) is one of the most severe craniosynostoses and is characterized by premature fusion of craniofacial sutures. Mutations of either Ser252Trp or Pro253Arg in fibroblast growth factor receptor 2 (FGFR2) are responsible for nearly all known cases of AS. Here we show that mutant mice carrying the activation mutation, Ser250Trp, which corresponds to Ser252Trp in human FGFR2, have malformations mimicking the skull abnormalities found in AS patients. Mutant mice (Fgfr2(250/+)) are smaller in body size with brachycephaly and exhibit distorted skulls with widely spaced eyes. Unexpectedly, the premature closure of the coronal suture is accompanied by decreased, rather than increased, bone formation. We demonstrate that the Fgfr2-Ser250Trp mutation does not cause obvious alterations in cell proliferation and differentiation; however, it results in increased Bax expression and apoptosis of osteogenic cells in mutant coronal suture. The accelerated cell death possibly reduces the space between osteogenic fronts of flat bones and results in the physical contact of these bones. Thus, our data reveal that dysregulated apoptosis plays an important role in the pathogenesis of AS related phenotypes. (C) 2003 Elsevier Inc. All rights reserved.