NEXN inhibits GATA4 and leads to atrial septal defects in mice and humans.

Abstract

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.

• Authors: Fan Yang, Lei Zhou, Qiguang Wang, Xin You, Ying Li, Yong Zhao, Xiaonan Han, Zai Chang, Xin He, Chunyan Cheng, Chong Wu, Wen-Jing Wang, Fang-Yuan Hu, Ting Zhao, Yang Li, Ming Zhao, Gu-Yan Zheng, Jie Dong, Chun Fan, Juxian Yang, Xianmin Meng, Youyi Zhang, Xianyang Zhu, Jingwei Xiong, Xiao-Li Tian, Huiqing Cao
• Journal: Cardiovascular research (Cardiovasc Res) Vol. 103 Issue 2 Pg. 228-37 (Jul 15 2014) ISSN: 1755-3245 [Electronic] England
• PMID: 24866383 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: [email protected].

Chemical References

• Actins
• GATA4 Transcription Factor
• GATA4 protein, human
• Gata4 protein, mouse
• Microfilament Proteins
• NEXN protein, human
• NEXN protein, mouse

Topics

• Actins (genetics)
• Animals
• GATA4 Transcription Factor (genetics, metabolism)
• Heart Defects, Congenital (genetics)
• Heart Septal Defects, Atrial (genetics)
• Humans
• Mice
• Microfilament Proteins (genetics, metabolism)
• Mutation (genetics)