机构：[1]Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China[2]Department of Cardiology, Shanghai Fifth People’s Hospital, Fudan University, Shanghai, China[3]Department of Cardiovascular Medicine, Tongji University School of Medicine, Shanghai, China[4]Department of Pediatrics, Tongji Hospital, Tongji University School of Medicine, Shanghai, China[5]Department of Emergency Medicine, Shanghai Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China[6]Department of Cardiovascular Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China[7]Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine, Shanghai, China[8]Department of Cardiovascular Research Laboratory, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China.
Aggregating evidence suggests that genetic determinants play a pivotal role in the pathogenesis of the congenitally bicuspid aortic valve (BAV). BAV is of pronounced genetic heterogeneity, and the genetic components underlying BAV in an overwhelming majority of patients remain elusive. In the current study, the whole coding exons and adjacent introns, as well as 5' and 3' untranslated regions of the GATA4 gene, which codes for a zinc-finger transcription factor crucial for the normal development of the aortic valve, were screened by direct sequencing in 150 index patients with congenital BAY. The available family members of an identified mutation carrier and 300 unrelated, ethnically matched healthy individuals used as controls were also genotyped for GATA4. The functional effect of the mutation was characterized using a dual-luciferase reporter assay system. As a result, a novel heterozygous GATA4 mutation, p.E147X, was identified in a family with BAV transmitted in an autosomal dominant pattern. The nonsense mutation was absent in 600 control chromosomes. Functional deciphers revealed that the mutant GATA4 protein lost transcriptional activity compared with its wild-type counterpart. Furthermore, the mutation disrupted the synergistic transcriptional activation between GATA4 and NKX2.5, another transcription factor responsible for BAY. In conclusion, this study associates. the GATA4 loss-of-function mutation with enhanced susceptibility to a BAV, thus providing novel insight into the molecular mechanism underpinning the BAY. (C) 2017 Elsevier Inc. All rights reserved.
基金：
National Natural Science Foundation of
China (81470372, 81400244, 81370400, and 81641014), the Natural Science
Foundation of Shanghai, China (15ZR1438100 and 16ZR1432500), the Medicine
Guided Program of Shanghai, China (17411971000), and the Fundamental
Research Funds for the Central Universities.
第一作者机构：[1]Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China
共同第一作者：
通讯作者：
通讯机构：[1]Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China[8]Department of Cardiovascular Research Laboratory, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China.
推荐引用方式(GB/T 7714)：
Li Ruo-Gu,Xu Ying-Jia,Wang Juan,et al.GATA4 Loss-of-Function Mutation and the Congenitally Bicuspid Aortic Valve[J].AMERICAN JOURNAL OF CARDIOLOGY.2018,121(4):469-474.doi:10.1016/j.amjcard.2017.11.012.
APA：
Li, Ruo-Gu,Xu, Ying-Jia,Wang, Juan,Liu, Xing-Yuan,Yuan, Fang...&Yang, Yi-Qing.(2018).GATA4 Loss-of-Function Mutation and the Congenitally Bicuspid Aortic Valve.AMERICAN JOURNAL OF CARDIOLOGY,121,(4)
MLA：
Li, Ruo-Gu,et al."GATA4 Loss-of-Function Mutation and the Congenitally Bicuspid Aortic Valve".AMERICAN JOURNAL OF CARDIOLOGY 121..4(2018):469-474
