title: Multiple synostoses syndrome is due to a missense mutation in exon 2 of FGF9 gene.
abstract: 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 wild-type 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.
authors: Model Organism Division, Department of Medical Genetics, E-Institutes of Shanghai Universities, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
authors: Xiao-Lin
authors: XL
authors: Wu
authors: Ming-Min
authors: MM
authors: Gu
authors: Lei
authors: L
authors: Huang
authors: Xue-Song
authors: XS
authors: Liu
authors: Hong-Xin
authors: HX
authors: Zhang
authors: Xiao-Yi
authors: XY
authors: Ding
authors: Jian-Qiang
authors: JQ
authors: Xu
authors: Bin
authors: B
authors: Cui
authors: Long
authors: L
authors: Wang
authors: Shun-Yuan
authors: SY
authors: Lu
authors: Xiao-Yi
authors: XY
authors: Chen
authors: Hai-Guo
authors: HG
authors: Zhang
authors: Wei
authors: W
authors: Huang
authors: Wen-Tao
authors: WT
authors: Yuan
authors: Jiang-Ming
authors: JM
authors: Yang
authors: Qun
authors: Q
authors: Gu
authors: Jian
authors: J
authors: Fei
authors: Zhu
authors: Z
authors: Chen
authors: Zhi-Min
authors: ZM
authors: Yuan
authors: Zhu-Gang
authors: ZG
authors: Wang
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D000818:Animals; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005091:Exons; D005260:Female; D051525:Fibroblast Growth Factor 9 / Q000737:chemistry / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010375:Pedigree; D015398:Signal Transduction; D013580:Synostosis / Q000235:genetics*
chemical_list: D051525:Fibroblast Growth Factor 9