一個(gè)家族五代人中居然有12個(gè)人患有不同程度的骨關(guān)節(jié)病,，上海的醫(yī)學(xué)專家終于為這一遺傳性疾病找到了“禍?zhǔn)?rdquo;―――基因突變。這一成果今天發(fā)表在國(guó)際人類遺傳學(xué)研究領(lǐng)域的頂級(jí)學(xué)術(shù)期刊《美國(guó)人類遺傳學(xué)雜志》網(wǎng)絡(luò)版上,。
這個(gè)家族患的是一種罕見(jiàn)的骨關(guān)節(jié)疾病,，名為多發(fā)性骨性連接綜合征（SYNS），是一類骨關(guān)節(jié)發(fā)育不全綜合征,，表現(xiàn)為常染色體顯性遺傳,。在這個(gè)家庭里,，發(fā)病關(guān)節(jié)多種多樣，有的是短指關(guān)節(jié),，有的是腳趾關(guān)節(jié),。課題組領(lǐng)銜專家、上海交通大學(xué)醫(yī)學(xué)院王鑄鋼教授解釋說(shuō)：“我們的發(fā)現(xiàn)糾正了過(guò)去人們對(duì)于此病的病因研究,。”
長(zhǎng)期以來(lái),，人們一直認(rèn)為該綜合征由位于17號(hào)染色體的NOG或位于20號(hào)染色體的生長(zhǎng)分化因子5（GDF5）基因突變所致。而課題組經(jīng)過(guò)多年的研究后發(fā)現(xiàn),，成纖維細(xì)胞生長(zhǎng)因子9（FGF9）基因的突變才是導(dǎo)致該家族SYNS的元兇,。
2004年，課題組在我國(guó)青海省發(fā)現(xiàn)了一個(gè)由五代共56人組成的SYNS大家系,。研究人員先后兩次赴青海進(jìn)行調(diào)研及樣本采集工作,。經(jīng)上海瑞金醫(yī)院骨科及放射科專家的檢查會(huì)診，發(fā)現(xiàn)該家族成員中共有12人患有不同程度的多發(fā)性骨關(guān)節(jié)融合,，如此規(guī)模的家系樣本在遺傳學(xué)研究領(lǐng)域?qū)崒俸币?jiàn),。
通過(guò)系統(tǒng)的遺傳學(xué)分析及基因突變檢測(cè)，并在國(guó)家人類基因組南方研究中心的配合下,，研究人員發(fā)現(xiàn),，與正常人的基因情況相比，這一家族患者體內(nèi)的突變體與其細(xì)胞膜表面受體的結(jié)合能力幾近喪失,，這使得細(xì)胞內(nèi)相關(guān)信號(hào)通路不能激活,，使骨髓間充質(zhì)干細(xì)胞或肋軟骨細(xì)胞的增殖速率減慢，削弱了軟骨細(xì)胞分化,、抑制了成骨細(xì)胞的活性等等,，并最終導(dǎo)致骨關(guān)節(jié)融合。
盡管這一成果主要是源于一個(gè)罕見(jiàn)的家族疾病,，但是,，被發(fā)現(xiàn)的這種致病突變基因與人類胚胎早期發(fā)育、骨關(guān)節(jié)形成及腫瘤發(fā)生都密切相關(guān),。揭示致病機(jī)理對(duì)骨關(guān)節(jié)發(fā)育機(jī)制研究,、骨關(guān)節(jié)疾病的診療防治等方面，都將具有十分重要的意義,。
該項(xiàng)研究成果由基礎(chǔ)醫(yī)學(xué)院王鑄鋼教授領(lǐng)銜,，共同第一作者吳曉林博士和顧鳴敏教授聯(lián)合附屬瑞金醫(yī)院、中科院上海生命科學(xué)院-交大醫(yī)學(xué)院健康科學(xué)研究所,、國(guó)家人類基因組南方研究中心,、上海南方模式生物研究中心等單位的數(shù)十位科研人員經(jīng)過(guò)5年協(xié)作攻關(guān)共同完成。（生物谷Bioon.com）
生物谷推薦原始出處：
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.
