Multiple synostoses syndrome is due to a missense mutation in exon 2 of FGF9 gene.
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.
Wu
Xiao-Lin
XL
Model Organism Division, Department of Medical Genetics, E-Institutes of Shanghai Universities, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
Gu
Ming-Min
MM
Huang
Lei
L
Liu
Xue-Song
XS
Zhang
Hong-Xin
HX
Ding
Xiao-Yi
XY
Xu
Jian-Qiang
JQ
Cui
Bin
B
Wang
Long
L
Lu
Shun-Yuan
SY
Chen
Xiao-Yi
XY
Zhang
Hai-Guo
HG
Huang
Wei
W
Yuan
Wen-Tao
WT
Yang
Jiang-Ming
JM
Gu
Qun
Q
Fei
Jian
J
Chen
Zhu
Z
Yuan
Zhi-Min
ZM
Wang
Zhu-Gang
ZG
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*
D051525:Fibroblast Growth Factor 9