GATA4 Loss-of-Function Mutations Underlie Familial Tetralogy of Fallot

Authors

  • Yi-Qing Yang,

    Corresponding author
    1. Department of Cardiology and Cardiovascular Research, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China
    • Correspondence to: Yi-Qing Yang, Department of Cardiology and Cardiovascular Research, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, China. E-mail: dryyq@tongji.edu.cn; Georges Nemer, Department of Biochemistry and Molecular Genetics, American University of Beirut, Beirut, Lebanon. E-mail: gn08@aub.edu.lb

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    • These authors contributed equally to this work.

  • Lara Gharibeh,

    1. Department of Biochemistry and Molecular Genetics, American University of Beirut, Beirut, Lebanon
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    • These authors contributed equally to this work.

  • Ruo-Gu Li,

    1. Department of Cardiology and Cardiovascular Research, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China
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  • Yuan-Feng Xin,

    1. Department of Cardiothoracic Surgery, East Hospital, Tongji University School of Medicine, Shanghai, China
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  • Juan Wang,

    1. Department of Cardiovascular Medicine, East Hospital, Tongji University School of Medicine, Shanghai, China
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  • Zhong-Min Liu,

    1. Department of Cardiothoracic Surgery, East Hospital, Tongji University School of Medicine, Shanghai, China
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  • Xing-Biao Qiu,

    1. Department of Cardiology and Cardiovascular Research, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China
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  • Ying-Jia Xu,

    1. Department of Cardiology and Cardiovascular Research, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China
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  • Lei Xu,

    1. Department of Cardiology and Cardiovascular Research, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China
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  • Xin-Kai Qu,

    1. Department of Cardiology and Cardiovascular Research, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China
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  • Xu Liu,

    1. Department of Cardiology and Cardiovascular Research, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China
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  • Wei-Yi Fang,

    1. Department of Cardiology and Cardiovascular Research, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China
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  • Ri-Tai Huang,

    1. Department of Cardiothoracic Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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  • Song Xue,

    1. Department of Cardiothoracic Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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  • Georges Nemer

    Corresponding author
    1. Department of Biochemistry and Molecular Genetics, American University of Beirut, Beirut, Lebanon
    • Correspondence to: Yi-Qing Yang, Department of Cardiology and Cardiovascular Research, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, China. E-mail: dryyq@tongji.edu.cn; Georges Nemer, Department of Biochemistry and Molecular Genetics, American University of Beirut, Beirut, Lebanon. E-mail: gn08@aub.edu.lb

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  • Contract grant sponsors: National Natural Science Fund of China (81070153, 81270161, 81271927); National Basic Research Program of China (2010CB912604); Personnel Development Foundation of Shanghai, China (2010019); Natural Science Fund of Shanghai, China (10ZR1428000); Key Program of Basic Research of Shanghai, China (10JC1414002); Medical Practice Plan (MPP) at the American University of Beirut.

  • Communicated by Jürgen Horst

ABSTRACT

Tetralogy of Fallot (TOF) represents the most common form of cyanotic congenital heart disease and accounts for significant morbidity and mortality in humans. Emerging evidence has implicated genetic defects in the pathogenesis of TOF. However, TOF is genetically heterogeneous and the genetic basis for TOF in most patients remains unclear. In this study, the GATA4 gene were sequenced in 52 probands with familial TOF, and three novel heterozygous mutations, including A9P and L51V both located in the putative first transactivational domain and N285S in the C-terminal zinc finger, were identified in three probands, respectively. Genetic analysis of the pedigrees demonstrated that in each family the mutation cosegregated with TOF with complete penetrance. The missense mutations were absent in 800 control chromosomes and the altered amino acids were highly conserved evolutionarily. Functional analysis showed that the GATA4 mutants were consistently associated with diminished DNA-binding affinity and decreased transcriptional activity. Furthermore, the N285S mutation completely disrupted the physical interaction between GATA4 and TBX5. To our knowledge, this report associates GATA4 loss-of-function mutations with familial TOF for the first time, providing novel insight into the molecular mechanism involved in TOF and suggesting potential implications for the early prophylaxis and allele-specific therapy of TOF.

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