title: NEXN inhibits GATA4 and leads to atrial septal defects in mice and humans.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Human Population Genetics, Institute of Molecular Medicine, Peking University, 5 Yiheyuan Rd., Beijing 100871, China.
authors.forename: Fan
authors.initials: F
authors.lastname: Yang
authors.affiliation: Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Qiguang
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Laboratory Medicine, The Affiliated Hospital of Yanbian University, Yanji, China.
authors.forename: Xin
authors.initials: X
authors.lastname: You
authors.affiliation: Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Li
authors.affiliation: Child Health and Development Institute, Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, NY, USA.
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Cincinnati Children's Hospital Medical Center (CCHMC), Cincinnati, OH, USA.
authors.forename: Xiaonan
authors.initials: X
authors.lastname: Han
authors.affiliation: School of Life Sciences, Tsinghua University, Beijing, China.
authors.forename: Zai
authors.initials: Z
authors.lastname: Chang
authors.affiliation: Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
authors.forename: Xin
authors.initials: X
authors.lastname: He
authors.affiliation: Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
authors.forename: Chunyan
authors.initials: C
authors.lastname: Cheng
authors.affiliation: Department of Human Population Genetics, Institute of Molecular Medicine, Peking University, 5 Yiheyuan Rd., Beijing 100871, China.
authors.forename: Chong
authors.initials: C
authors.lastname: Wu
authors.affiliation: Department of Human Population Genetics, Institute of Molecular Medicine, Peking University, 5 Yiheyuan Rd., Beijing 100871, China.
authors.forename: Wen-Jing
authors.initials: WJ
authors.lastname: Wang
authors.affiliation: Department of Human Population Genetics, Institute of Molecular Medicine, Peking University, 5 Yiheyuan Rd., Beijing 100871, China.
authors.forename: Fang-Yuan
authors.initials: FY
authors.lastname: Hu
authors.affiliation: Department of Human Population Genetics, Institute of Molecular Medicine, Peking University, 5 Yiheyuan Rd., Beijing 100871, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Zhao
authors.affiliation: Department of Human Population Genetics, Institute of Molecular Medicine, Peking University, 5 Yiheyuan Rd., Beijing 100871, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Zhao
authors.affiliation: Department of Human Population Genetics, Institute of Molecular Medicine, Peking University, 5 Yiheyuan Rd., Beijing 100871, China.
authors.forename: Gu-Yan
authors.initials: GY
authors.lastname: Zheng
authors.affiliation: Department of Human Population Genetics, Institute of Molecular Medicine, Peking University, 5 Yiheyuan Rd., Beijing 100871, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Dong
authors.affiliation: Lerner Research Institute, The Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Chun
authors.initials: C
authors.lastname: Fan
authors.affiliation: Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Juxian
authors.initials: J
authors.lastname: Yang
authors.affiliation: Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Xianmin
authors.initials: X
authors.lastname: Meng
authors.affiliation: Institute of Vascular Medicine, Peking University Third Hospital and Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Beijing, China.
authors.forename: Youyi
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Congenital Heart Disease, General Hospital of Shenyang Military Area Command, Shenyang, China.
authors.forename: Xianyang
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Department of Human Population Genetics, Institute of Molecular Medicine, Peking University, 5 Yiheyuan Rd., Beijing 100871, China.
authors.forename: Jingwei
authors.initials: J
authors.lastname: Xiong
authors.affiliation: Department of Human Population Genetics, Institute of Molecular Medicine, Peking University, 5 Yiheyuan Rd., Beijing 100871, China tianxiaoli@pku.edu.cn caohuiqing@pku.edu.cn.
authors.forename: Xiao-Li
authors.initials: XL
authors.lastname: Tian
authors.affiliation: Department of Human Population Genetics, Institute of Molecular Medicine, Peking University, 5 Yiheyuan Rd., Beijing 100871, China tianxiaoli@pku.edu.cn caohuiqing@pku.edu.cn.
authors.forename: Huiqing
authors.initials: H
authors.lastname: Cao
mesh_terms: D000199:Actins / Q000235:genetics; D000818:Animals; D050991:GATA4 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D006330:Heart Defects, Congenital / Q000235:genetics; D006344:Heart Septal Defects, Atrial / Q000235:genetics*; D006801:Humans; D051379:Mice; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism*; D009154:Mutation / Q000235:genetics*
chemical_list: D000199:Actins; D050991:GATA4 Transcription Factor; C484170:GATA4 protein, human; C484171:Gata4 protein, mouse; D008840:Microfilament Proteins; C501659:NEXN protein, human; C000597957:NEXN protein, mouse
keywords: Actin; Atrial septal defect; GATA4; Mutation; NEXN