Functions of fibroblast growth factor receptors

在这里，我们报告了我们对骨骼疾病之一的研究，Apert综合征，它发生在人类65,000个活产儿中。我们首先将在人类Apert患者中发现的Ser252Trp突变引入小鼠FGFR2基因。FGFR2-Ser252Trp突变小鼠显示出模仿人类Apert病的表型。然后我们用这个老鼠模型来测试预防治疗方法，看看这种疾病是否可以预防或治愈。我们发现，在该小鼠模型中，靶向FGFR2-S252W突变形式mRNA的小发夹RNA （shRNA）完全抑制apert样颅缝闭锁和相关缺陷。我们进一步表明，正常FGFR2信号的恢复表现为ERK12活性的改变，暗示ERK及其下游基因参与疾病表达。此外，用ERK抑制剂治疗突变小鼠可以完全治愈突变表型。这些结果说明了ERK激活在fgfr2 - s252w相关颅缝闭闭中未知的致病作用，并代表了shrna介导治疗由人类基因组激活点突变相关功能获得引起的疾病的新概念。

Here we report our study on one of the skeletal diseases, the Apert syndrome, which occurs at one in 65,000 live births in human. We first introduced a Ser252Trp mutation that is found in human Apert patients, to mouse FGFR2 gene. The FGFR2-Ser252Trp mutant mice displayed phenotypes mimicking the human Apert disease. We then use this mouse model to test preventivetherapeutic approaches to see if the disease can be prevented or cured. We show that a small hairpin RNA (shRNA), targeting the FGFR2-S252W mutant form mRNA in this mouse model, completely inhibits Apert-like craniosynostosis and the related defects. We further show that restoration of normal FGFR2 signaling is manifested by an alteration of ERK12 activity, implicating ERK and its downstream genes in disease expressivity. Furthermore, treatment of mutant mice with an ERK inhibitor results in a complete cure of mutant phenotypes. These results illustrate an unknown pathogenic role of ERK activation in the FGFR2-S252W-associated craniosynostosis and represent a new concept of shRNA-mediated therapy for diseases caused by gain of functions associated with activating point mutations in human genome.