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学科主题: 临床医学
题名:
NEXN inhibits GATA4 and leads to atrial septal defects in mice and humans
作者: 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
发表日期: 2014-07-15
DOI: 10.1093/cvr/cvu134
卷: 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
所属项目编号: 81170097 ; 2010CB529503
项目资助者: National Natural Science Foundation of China (NSFC) ; Chinese Ministry of Science and Technology
WOS记录号: WOS:000340054800008
Citation statistics:
内容类型: 期刊论文
URI标识: http://ir.bjmu.edu.cn/handle/400002259/52440
Appears in Collections:北京大学第三临床医学院_心血管内科_期刊论文

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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

Recommended Citation:
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-+.
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