A Novel Missense Mutation of GATA4 in a Chinese Family with Congenital Heart Disease

被引:18
作者
Zhang, Xiaoqing [1 ]
Wang, Jian [1 ]
Wang, Bo [1 ]
Chen, Sun [2 ]
Fu, Qihua [1 ]
Sun, Kun [2 ]
机构
[1] Shanghai Jiao Tong Univ, Sch Med, Shanghai Childrens Med Ctr, Dept Lab Med, Shanghai, Peoples R China
[2] Shanghai Jiao Tong Univ, Sch Med, Xinhua Hosp, Dept Pediat Cardiol, Shanghai, Peoples R China
来源
PLOS ONE | 2016年 / 11卷 / 07期
基金
中国国家自然科学基金;
关键词
VENTRICULAR SEPTAL-DEFECT; TETRALOGY; FALLOT; REGULATOR; GENE;
D O I
10.1371/journal.pone.0158904
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Background Congenital heart disease (CHD) is the most prevalent type of birth defect in human, with high morbidity in infant. Several genes essential for heart development have been identified. GATA4 is a pivotal transcription factor that can regulate the cardiac development. Many GATA4 mutations have been identified in patients with different types of CHD. Aims In this study, the NKX2-5, HAND1 and GATA4 coding regions were sequenced in a family spanning three generations in which seven patients had CHD. Disease-causing potential variation in this family was evaluated by bioinformatics programs and the transcriptional activity of mutant protein was analyzed by the dual luciferase reporter assay. Results A novel GATA4 mutation, c.C931T (p.R311W), was identified and co-segregated with the affected patients in this family. The bioinformatics programs predicted this heterozygous mutation to be deleterious and the cross-species alignment of GATA4 sequences showed that the mutation occurred within a highly conserved amino acid. Even though it resided in the nuclear localization signal domain, the mutant protein didn't alter its intracellular distribution. Nevertheless, further luciferase reporter assay demonstrated that the p.R311W mutation reduced the ability of GATA4 to activate its downstream target gene. Conclusions Our study identified a novel mutation in GATA4 that likely contributed to the CHD in this family. This finding expanded the spectrum of GATA4 mutations and underscored the pathogenic correlation between GATA4 mutations and CHD.
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页数:11
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共 29 条
  • [1] Molecular insight into heart development and congenital heart disease: An update review from the Arab countries
    Aburawi, Elhadi H.
    Aburawi, Hanan E.
    Bagnall, Keith M.
    Bhuiyan, Zahurul A.
    [J]. TRENDS IN CARDIOVASCULAR MEDICINE, 2015, 25 (04) : 291 - 301
  • [2] A GATA4-regulated tumor suppressor network represses formation of malignant human astrocytomas
    Agnihotri, Sameer
    Wolf, Amparo
    Munoz, Diana M.
    Smith, Christopher J.
    Gajadhar, Aaron
    Restrepo, Andres
    Clarke, Ian D.
    Fuller, Gregory N.
    Kesari, Santosh
    Dirks, Peter B.
    McGlade, C. Jane
    Stanford, William L.
    Aldape, Kenneth
    Mischel, Paul S.
    Hawkins, Cynthia
    Guha, Abhijit
    [J]. JOURNAL OF EXPERIMENTAL MEDICINE, 2011, 208 (04) : 689 - 702
  • [3] The developmental genetics of congenital heart disease
    Bruneau, Benoit G.
    [J]. NATURE, 2008, 451 (7181) : 943 - 948
  • [4] GATA4 Mutations in Chinese Patients with Congenital Cardiac Septal Defects
    Chen, Ming-wu
    Pang, Yu-sheng
    Guo, Ying
    Pan, Jia-hua
    Liu, Bing-li
    Shen, Jie
    Liu, Tang-wei
    [J]. PEDIATRIC CARDIOLOGY, 2010, 31 (01) : 85 - 89
  • [5] Recent advances in cardiac development with therapeutic implications for adult cardiovascular disease
    Epstein, JA
    Parmacek, MS
    [J]. CIRCULATION, 2005, 112 (04) : 592 - 597
  • [6] Chemical Biology of Protein Arginine Modifications in Epigenetic Regulation
    Fuhrmann, Jakob
    Clancy, Kathleen W.
    Thompson, Paul R.
    [J]. CHEMICAL REVIEWS, 2015, 115 (11) : 5413 - 5461
  • [7] GATA4 mutations cause human congenital heart defects and reveal an interaction with TBX5
    Garg, V
    Kathiriyra, IS
    Barnes, R
    Schluterman, MK
    King, IN
    Butler, CA
    Rothrock, CR
    Eapen, RS
    Hirayama-Yamada, K
    Joo, K
    Matsuoka, R
    Cohen, JC
    Srivastava, D
    [J]. NATURE, 2003, 424 (6947) : 443 - 447
  • [8] NKX2.5 mutations in patients with tetralogy of Fallot
    Goldmuntz, E
    Geiger, E
    Benson, DW
    [J]. CIRCULATION, 2001, 104 (21) : 2565 - 2568
  • [9] Heineke J, 2007, J CLIN INVEST, V117, P3198, DOI 10.1172/JCI32573
  • [10] Induction of cardiomyocytes by GATA4 in Xenopus ectodermal explants
    Latinkic, BV
    Kotecha, S
    Mohun, TJ
    [J]. DEVELOPMENT, 2003, 130 (16): : 3865 - 3876