王晶^1，， 白婷婷^2，， 严金婷^3，， 王彬彬^4，， 刘世明^5，， 陈秋红^5，， 谢小冬^6，，王熙^4，， 吴施楠^4，， 张薇^4，， 潘虹^4，*

（  1、首都医科大学基础医学院医学遗传学与发育生物学学系；       2、四川省成都医学院第一附属医院；       3、中国科学院北京基因组所；       4、国家卫生计生委科学技术研究所；       5、青海高原心血管病研究所；       6、兰州大学生命科学学院；  ）

摘要： 在先天性心脏缺陷（CHD）中，室间隔缺损（VSD）是发病最广的亚型。以往的研究表明，生长/分化因子1（GDF1）的突变对先天性心脏病的发生具有重要影响。本研究探讨了GDF1在VSD发病中的作用。通过与对照组和公共数据库进行比对，我们在312例中国VSD病人中发现了一个25 bp的缺失（截短突变），5个非同义突变（2个位于蛋白质编码区域）， 和一个在5'-UTR处的异常变异。通过双荧光素酶检测发现，5'-UTR中变异的C.-47G> C基因影响了GDF1启动子激活转录的能力。与此同时，位于成熟肽区域的p.A266T和p.P312T的突变也会抑制CAGA-Luc的活化。CAGA-Luc 是TGFβ信号传导途径的应答分子。我们的研究为GDF1基因突变可能与VSD的发生有关提供了重要的证据
关键词： GDF 1; VSD; 基因突变

Wang Jing^1,， Bai Tingting^2,， Yan Jinting^3,， Wang Binbin^4,， Liu Shiming^5,，Chen Qiuhong^5,， Xie Xiaodong^6,， Wang Xi^4,， Wu Shinan^7,， Zhang Wei^7,， Pan Hong^7,*

（  1、Department of Medical Genetics, School of Basic Medical Sciences, Capital Medical University, Beijing, China；       2、The First Affiliated Hospital of Chengdu Medical College, Sichuan, China；      3、CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China；       4、National Research Institute for Family Planning, Beijing, China；      5、Qinghai Cardiovascular Diseases Vocational Hospital, Xining, China；       6、School of Life Science, Lanzhou University, Lanzhou, China；       7、 National Research Institute for Family Planning, Beijing, China；  ）

Abstract： Ventricular septal defect (VSD) is the largest subtype of congenital heart defect (CHD). Previous studies have suggested that mutations of growth/differentiation factor 1 (GDF1) contribute to CHD. This study explored the role of GDF1 in the etiology of VSD. A total of 312 VSD Chinese patients and 250 healthy controls were screened for mutations in the GDF1 gene. Compared with the controls and the public database, one 25-bp deletion (truncation mutation), five point non-synonymous mutations (two located in the protein coding region), and one variant in the 5′-UTR were found in 312 VSD Chinese patients. The dual luciferase assays showed that the c.-47G>C mutation in the 5′-UTR affected the capacity of GDF1 promoter to activate transcription. In the meanwhile, the p.A266T and p.P312T mutations in the mature peptide region repressed the activation of the CAGA-Luc reporter which was the responsive reporter of TGFβ signaling pathway. Our study provides important evidence that GDF1 gene mutations might be associated with VSD.
Keywords： kGDF 1; VSD; Gene Mutation 

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