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Multiple Synostoses Syndrome Is Due to a Missense Mutation in Exon 2 of FGF9 Gene |
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| Authors: | Xiao-lin Wu Ming-min Gu Lei Huang Hong-xin Zhang Jian-qiang Xu Long Wang Shun-yuan Lu Xiao-yi Chen Wei Huang Jiang-ming Yang Jian Fei Zhi-min Yuan |
| Institution: | 1 Model Organism Division, Department of Medical Genetics, E-Institutes of Shanghai Universities, Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai 200025, China 2 Laboratory of Genetic Engineering, Institute of Health Sciences, Shanghai Institutes for Biological Sciences of Chinese Academy of Sciences and SJTUSM, Shanghai 200025, China 3 Department of Radiology, Rui-jin Hospital, SJTUSM, Shanghai 200025, China 4 Department of Orthopaedics, Rui-jin Hospital, SJTUSM, Shanghai 200025, China 5 Department of Endocrinology, Rui-jin Hospital, SJTUSM, Shanghai 200025, China 6 State Key Laboratory of Medical Genomics, Rui-jin Hospital, SJTUSM, Shanghai 200025, China 7 Shanghai Research Centre for Model Organisms, Shanghai 201210, China 8 Chinese National Human Genome Centre at Shanghai, Shanghai 201203, China 9 Department of Inspect, Qinghai Chinese Medical Hospital, Xining 810000, China 10 Radiation Biology Division, Department of Radiation Oncology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA |
| 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 FGF9S99N is expressed and secreted as efficiently as wild-type FGF9 in transfected cells. However, FGF9S99N 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 β-catenin and c-Myc expression when compared with wild-type FGF9. Importantly, the binding of FGF9S99N 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. |
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