Functions of fibroblast growth factor receptors

在这里，我们报告了我们对骨骼疾病之一，Apert综合征的研究，该综合征在65，000例活产婴儿中发生。我们首先将在人类Apert患者中发现的Ser 252 Trp突变引入小鼠FGFR 2基因。FGFR 2-Ser 252 Trp突变小鼠表现出模仿人类Apert病的表型。然后，我们使用这种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，在该小鼠模型中，靶向FGFR 2-S252 W突变形式mRNA的小发夹RNA（shRNA）完全抑制了类颅缝早闭和相关缺陷。我们进一步表明，正常FGFR 2信号的恢复表现为ERK 12活性的改变，涉及ERK及其下游基因的疾病表达。此外，用ERK抑制剂治疗突变小鼠导致突变表型的完全治愈。这些结果阐明了ERK激活在FGFR 2-S252 W相关颅缝早闭症中的未知致病作用，并代表了shRNA介导的治疗由人类基因组中与激活点突变相关的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.