BMP4基因稀有突变与先天性心脏病易感性的相关性研究  

Association Study between BMP4 Rare Mutations and Susceptibility to Congenital Heart Disease

作　　者：彭瑞 李培强[3] 程良平 郑煜芳[1,2] 王红艳 周翔宇[1,2] Peng Rui;Li Peiqiang;Cheng Liangping;Zheng Yufang;Wang Hongyan;Zhou Xiangyu(School of Life Sciences,Fudan University,Shanghai,200438;Obstetrics and Gynecology Hospital,Fudan University,Shanghai,200011;School of Basic Medical Sciences,Lanzhou University,Lanzhou,730000;Children＇s Hospital of Chongqing Medical University,Chongqing,400016)

机构地区：[1]复旦大学生命科学学院,上海200438 [2]复旦大学附属妇产科医院,上海200011 [3]兰州大学基础医学院,兰州730000 [4]重庆医科大学附属儿童医院,重庆400016

出　　处：《基因组学与应用生物学》2018年第8期3605-3610,共6页Genomics and Applied Biology

基　　金：国家重大科学研究计划(NO.2012CB945403);国家自然科学青年基金(NO.81601283)共同资助

摘　　要：小鼠模型研究已表明骨形态发生蛋白4（Bmp4）缺陷引起心脏结构异常等表型。为了进一步探索BMP4基因新发稀有错义突变与中国汉族人群中先天性心脏病（congenital heart disease,CHD）发生的相关性,本实验中我们选取来自山东的417例CHD患者血液样本和213例正常对照样本,利用靶向捕获技术对BMP4基因编码区进行深度测序。我们一共检测到5个病例特有的稀有突变位点,其中3个错义突变（c.326G〉T,c.485G〉A,c.632G〉A）在公共数据库中没有记录,且在不同物种中高度保守。双荧光素酶报告基因实验结果表明c.326G〉T和c.632G〉A显著下调NIH3T3细胞的BMP信号通路的活性。我们的研究表明BMP4中新发现的病例特有的稀有错义突变可能通过下调BMP信号通路活性而导致先天性心脏病的发生。Previous studies in mice model have demonstated that Bmp4 deficiency cause abnormalities in cardiac structure.To further study the associations between missense mutations of BMP4 and the susceptibility to congenital heart disease（CHD）,we sequenced coding region of BMP4 in 417 CHD cases and 213 controls from Shandong province by target capture technology.We identified a total of 5 case-specific variants in coding region of BMP4.Among them,3 missense mutations（c.326 GT,c.485 GA,c.632 GA） represent novel forms in public database and were highly conserved in different species.The result of dual-luciferase reporter assay indicated that c.326 GT and c.632 GA significantly down-regulate the activity of BMP signal pathway.Our study suggests that case-specific novel rare missense mutations in BMP4 contribute to CHD via regulating BMP signal pathway activity.

关 键 词：先天性心脏病(CHD) BMP信号通路 BMP4 靶向捕获技术 双荧光素酶报告基因实验 

分 类 号：R541.1[医药卫生—心血管疾病]