Multiple Synostoses Syndrome Is Due to a Missense Mutation in Exon 2 of FGF9 Gene
Multiple Synostoses Syndrome Is Due to a Missense Mutation in Exon 2 of FGF9 Gene
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多发性骨性联结综合征是由 FGF9 基因外显子 2 错义突变引起
DOI：
10.1016/j.ajhg.2009.06.007
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发表时间：
2009-07-10
影响因子：
9.8
通讯作者：
Wang, Zhu-gang
中科院分区：
文献类型：
--
作者：
Wu, Xiao-lin;Gu, Ming-min;Wang, Zhu-gang
成纤维细胞生长因子（FGF）在几个发育过程中发挥着不同的作用。导致FGF信号失调的突变可导致人类骨骼发育不良和癌症。（1，2）我们报道了一个中国多发性骨性结合综合征（SYNS）家系中12例患者的FGF 9基因第2外显子的错义突变（Ser 99 Asp）。体外研究表明，FGF 9（S99 N）在转染细胞中与野生型FGF 9一样有效地表达和分泌。然而，FGF 9（S99 N）诱导受损的软骨细胞增殖和分化，这伴随着骨髓源性间充质干细胞（BMSC）的成骨分化和基质矿化的增强。生化分析显示，与野生型FGF 9相比，FGF 9中的S99 N突变导致FGF信号传导显著受损，如Erk 1/2途径活性降低以及β-连环蛋白和c-Myc表达降低所证明的。重要的是，FGF 9（S99 N）与其受体的结合严重受损，尽管突变型FGF 9本身或与野生型FGF 9的二聚化能力未受到可检测的影响，这为缺陷性FGFR信号传导提供了基础。总的来说，我们的数据表明，以前未表征的FGF 9突变是SYNS的原因之一，暗示了FGF 9在正常关节发育中的重要作用。
Fibroblast growth factors (FGFs) play diverse roles in several developmental processes. Mutations leading to deregulated FGF signaling can cause human skeletal dysplasias and cancer.(1,2) Here we report a missense mutation (Ser99Asp) in exon 2 of FGF9 in 12 patients with multiple synostoses syndrome (SYNS) in a large Chinese family. In vitro studies demonstrate that FGF9(S99N) is expressed and secreted as efficiently as wild-type FGF9 in transfected cells. However, FGF9(S99N) induces compromised chondrocyte proliferation and differentiation, which is accompanied by enhanced osteogenic differentiation and matrix mineralization of bone marrow-derived mesenchymal stem cells (BMSCs). Biochemical analysis reveals that S99N mutation in FGF9 leads to significantly impaired FGF signaling, as evidenced by diminished activity of Erk1/2 pathway and decreased beta-catenin and c-Myc expression when compared with wild-type FGF9. Importantly, the binding of FGF9(S99N) to its receptor is severely impaired although the dimerization ability of mutant FGF9 itself or with wildtype FGF9 is not detectably affected, providing a basis for the defective FGFR signaling. Collectively, our data demonstrate a previously uncharacterized mutation in FGF9 as one of the causes of SYNS, implicating an important role of FGF9 in normal joint development.