IR@PKUHSC  > 北京大学第三临床医学院  > 心血管内科
学科主题临床医学
NEXN inhibits GATA4 and leads to atrial septal defects in mice and humans
Yang, Fan1; Zhou, Lei2; Wang, Qiguang3; You, Xin4; Li, Ying2; Zhao, Yong5; Han, Xiaonan6; Chang, Zai7; He, Xin2; Cheng, Chunyan2; Wu, Chong1; Wang, Wen-Jing1; Hu, Fang-Yuan1; Zhao, Ting1; Li, Yang1; Zhao, Ming3; Zheng, Gu-Yan1; Dong, Jie1; Fan, Chun8; Yang, Juxian9,10; Meng, Xianmin9,10; Zhang, Youyi11,12; Zhu, Xianyang13; Xiong, Jingwei1; Tian, Xiao-Li1; Cao, Huiqing1
关键词Atrial Septal Defect Nexn Gata4 Actin Mutation
刊名CARDIOVASCULAR RESEARCH
2014-07-15
DOI10.1093/cvr/cvu134
103期:2页:228-+
收录类别SCI
文章类型Article
WOS标题词Science & Technology
类目[WOS]Cardiac & Cardiovascular Systems
研究领域[WOS]Cardiovascular System & Cardiology
关键词[WOS]RANDOMIZED CONTROLLED-TRIAL ; ACUTE MYOCARDIAL-INFARCTION ; GLUCOSE-INSULIN-POTASSIUM ; OXIDE SYNTHASE PHOSPHORYLATION ; EMBRYONIC STEM-CELLS ; TRANSCRIPTION FACTOR ; CARDIOMYOCYTE DIFFERENTIATION ; FUNCTIONAL RECOVERY ; HEART-DISEASE ; HYPERGLYCEMIA
英文摘要

Aims Cardiac structural genes have been implicated as causative factors for congenital heart diseases (CHDs). NEXN is an F-actin binding protein and previously identified as a disease gene causing cardiomyopathies. Whether NEXN contributes to CHDs aetiologically remains unknown. Here, we explored the function of NEXN in cardiac development.

Methods and results First, we determine the role of NEXN in cardiac differentiation using mouse P19cl6 in vitro model; we demonstrated that NEXN inhibited cardiac contractile markers, serving as a negative regulator. Interestingly, we found this effect was mediated by GATA4, a crucial transcription factor that controls cardiac development by knockdown, overexpression, and rescue experiment, respectively. We then generated transgenic mouse models and surprisingly, we discovered cardiac-selective expression of the NEXN gene caused atrial septal defects (ASDs). Next, to search for the mutations in NEXN gene in patients suffering from ASDs, we sequenced the exon and exon-intron joint regions of the NEXN gene in 150 probands with isolated ASDs and identified three mutations in the conserved region of NEXN (c.-52-78C>A, K199E, and L227S), which were not found in 500 healthy controls. Finally, we characterize the related mechanisms and found all mutations inhibited GATA4 expression.

Conclusion We identify NEXN as a novel gene for ASD and its function to inhibit GATA4 established a critical regulation of an F-actin binding protein on a transcription factor in cardiac development.

语种英语
WOS记录号WOS:000340054800008
项目编号81170097 ; 2010CB529503
资助机构National Natural Science Foundation of China (NSFC) ; Chinese Ministry of Science and Technology
引用统计
被引频次:4[WOS]   [WOS记录]     [WOS相关记录]
文献类型期刊论文
条目标识符http://ir.bjmu.edu.cn/handle/400002259/52440
专题北京大学第三临床医学院_心血管内科
北京大学药学院_化学生物学系
作者单位1.Tsinghua Univ, Sch Life Sci, Beijing 100084, Peoples R China
2.Cleveland Clin, Lerner Res Inst, Cleveland, OH 44106 USA
3.Peking Univ, Inst Mol Med, Dept Human Populat Genet, Beijing 100871, Peoples R China
4.Nanjing Med Univ, Affiliated Hosp 1, Dept Cardiol, Nanjing, Jiangsu, Peoples R China
5.Fourth Mil Med Univ, Dept Cardiol, Xijing Hosp, Xian 710032, Peoples R China
6.Yanbian Univ, Affiliated Hosp, Dept Lab Med, Yanji, Peoples R China
7.Mt Sinai Sch Med, Child Hlth & Dev Inst, Dept Genet & Genom Sci, New York, NY USA
8.Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH 45229 USA
9.Chinese Acad Med Sci, Fuwai Hosp, Natl Ctr Cardiovasc Dis, Beijing 100730, Peoples R China
10.Peking Union Med Coll, Beijing 100021, Peoples R China
11.Peking Univ, Inst Vasc Med, Hosp 3, Beijing 100871, Peoples R China
12.Minist Educ, Key Lab Mol Cardiovasc Sci, Beijing, Peoples R China
13.Gen Hosp, Shenyang Mil Area Command, Dept Congenital Heart Dis, Shenyang, Peoples R China
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Yang, Fan,Zhou, Lei,Wang, Qiguang,et al. NEXN inhibits GATA4 and leads to atrial septal defects in mice and humans[J]. CARDIOVASCULAR RESEARCH,2014,103(2):228-+.
APA Yang, Fan.,Zhou, Lei.,Wang, Qiguang.,You, Xin.,Li, Ying.,...&Cao, Huiqing.(2014).NEXN inhibits GATA4 and leads to atrial septal defects in mice and humans.CARDIOVASCULAR RESEARCH,103(2),228-+.
MLA Yang, Fan,et al."NEXN inhibits GATA4 and leads to atrial septal defects in mice and humans".CARDIOVASCULAR RESEARCH 103.2(2014):228-+.
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