一个家族五代人中居然有12个人患有不同程度的骨关节病，上海的医学专家终于为这一遗传性疾病找到了“祸首”―――基因突变。这一成果今天发表在国际人类遗传学研究领域的顶级学术期刊《美国人类遗传学杂志》网络版上。
这个家族患的是一种罕见的骨关节疾病，名为多发性骨性连接综合征（SYNS），是一类骨关节发育不全综合征，表现为常染色体显性遗传。在这个家庭里，发病关节多种多样，有的是短指关节，有的是脚趾关节。课题组领衔专家、上海交通大学医学院王铸钢教授解释说：“我们的发现纠正了过去人们对于此病的病因研究。”
长期以来，人们一直认为该综合征由位于17号染色体的NOG或位于20号染色体的生长分化因子5（GDF5）基因突变所致。而课题组经过多年的研究后发现，成纤维细胞生长因子9（FGF9）基因的突变才是导致该家族SYNS的元凶。
2004年，课题组在我国青海省发现了一个由五代共56人组成的SYNS大家系。研究人员先后两次赴青海进行调研及样本采集工作。经上海瑞金医院骨科及放射科专家的检查会诊，发现该家族成员中共有12人患有不同程度的多发性骨关节融合，如此规模的家系样本在遗传学研究领域实属罕见。
通过系统的遗传学分析及基因突变检测，并在国家人类基因组南方研究中心的配合下，研究人员发现，与正常人的基因情况相比，这一家族患者体内的突变体与其细胞膜表面受体的结合能力几近丧失，这使得细胞内相关信号通路不能激活，使骨髓间充质干细胞或肋软骨细胞的增殖速率减慢，削弱了软骨细胞分化、抑制了成骨细胞的活性等等，并最终导致骨关节融合。
尽管这一成果主要是源于一个罕见的家族疾病，但是，被发现的这种致病突变基因与人类胚胎早期发育、骨关节形成及肿瘤发生都密切相关。揭示致病机理对骨关节发育机制研究、骨关节疾病的诊疗防治等方面，都将具有十分重要的意义。
该项研究成果由基础医学院王铸钢教授领衔，共同第一作者吴晓林博士和顾鸣敏教授联合附属瑞金医院、中科院上海生命科学院-交大医学院健康科学研究所、国家人类基因组南方研究中心、上海南方模式生物研究中心等单位的数十位科研人员经过5年协作攻关共同完成。（生物谷Bioon.com）
生物谷推荐原始出处：
The American Journal of Human Genetics, 10 July 2009 doi:10.1016/j.ajhg.2009.06.007
Multiple Synostoses Syndrome Is Due to a Missense Mutation in Exon 2 of FGF9 Gene
Xiao-lin Wu1,11,Ming-min Gu1,11,Lei Huang1,Xue-song Liu1,2,Hong-xin Zhang1,Xiao-yi Ding3,Jian-qiang Xu4,Bin Cui5,Long Wang2,6,7,Shun-yuan Lu2,6,7,Xiao-yi Chen1,Hai-guo Zhang1,Wei Huang8,Wen-tao Yuan8,Jiang-ming Yang9,Qun Gu9,Jian Fei7,Zhu Chen6,8,Zhi-min Yuan10andZhu-gang Wang1,2,6,7,,
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
Fibroblast growth factors (FGFs) play diverse roles in several developmental processes. Mutations leading to deregulated FGF signaling can cause human skeletal dysplasias and cancer., 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 -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.
