Functions of fibroblast growth factor receptors

在这里，我们报告了我们对骨骼疾病之一的Apert综合征的研究，这种疾病在人类每65,000名活产儿中就有一例发生。我们首次将在人类Apert患者中发现的Ser252Trp突变引入小鼠FGFR2基因。FGFR2-Ser252Trp突变小鼠表现出与人类Apert病相似的表型。然后，我们使用这个小鼠模型来测试预防和治疗方法，看看这种疾病是否可以预防或治愈。我们发现在这个小鼠模型中，针对FGFR2-S252W突变形式的mRNA的小发夹RNA(ShRNA)完全抑制了Apert样颅性融合和相关的缺陷。我们进一步表明，正常的FGFR2信号的恢复表现为ERK12活性的改变，这表明ERK及其下游基因参与了疾病的表达。此外，用ERK抑制剂治疗突变小鼠可以完全治愈突变表型。这些结果阐明了ERK激活在FGFR2-S252W相关性颅缝融合中的未知致病作用，并代表了shRNA介导的疾病治疗的新概念，这些疾病是由于获得了与激活人类基因组点突变相关的功能而引起的。

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.