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  • Mutations in Cardiac T-Box Factor Gene TBX20 are associated with Diverse Cardiac Pathologies, Including Defects of Septation and Valvulogenesis and Cardiomyopathy

    Author(s)
    P. Kirk, Edwin
    Sunde, Margaret
    W. Costa, Mauro
    Rankin, Scott
    Wolstein, Orit
    Leticia Castro, M.
    L. Butler, Tanya
    Hyun, Changbaig
    Guo, Guanglan
    Otway, Robyn
    Mackay, Joel P.
    B. Waddell, Leigh
    D. Cole, Andrew
    Hayward, Christopher
    Keogh, Anne
    Macdonald, Peter
    Griffiths, Lyn
    Fatkin, Dianne
    F. Sholler, Gary
    M. Zorn, Aaron
    P. Feneley, Michael
    S. Winlaw, David
    P. Harvey, Richard
    Griffith University Author(s)
    Griffiths, Lyn
    Year published
    2007
    Metadata
    Show full item record
    Abstract
    The T-box family transcription factor gene TBX20 acts in a conserved regulatory network, guiding heart formation and patterning in diverse species. Mouse Tbx20 is expressed in cardiac progenitor cells, differentiating cardiomyocytes, and developing valvular tissue, and its deletion or RNA interference-mediated knockdown is catastrophic for heart development. TBX20 interacts physically, functionally, and genetically with other cardiac transcription factors, including NKX2- 5, GATA4, and TBX5, mutations of which cause congenital heart disease (CHD). Here, we report nonsense (Q195X) and missense (I152M) germline mutations within ...
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    The T-box family transcription factor gene TBX20 acts in a conserved regulatory network, guiding heart formation and patterning in diverse species. Mouse Tbx20 is expressed in cardiac progenitor cells, differentiating cardiomyocytes, and developing valvular tissue, and its deletion or RNA interference-mediated knockdown is catastrophic for heart development. TBX20 interacts physically, functionally, and genetically with other cardiac transcription factors, including NKX2- 5, GATA4, and TBX5, mutations of which cause congenital heart disease (CHD). Here, we report nonsense (Q195X) and missense (I152M) germline mutations within the T-box DNA-binding domain of human TBX20 that were associated with a family history of CHD and a complex spectrum of developmental anomalies, including defects in septation, chamber growth, and valvulogenesis. Biophysical characterization of wild-type and mutant proteins indicated how the missense mutation disrupts the structure and function of the TBX20 T-box. Dilated cardiomyopathy was a feature of the TBX20 mutant phenotype in humans and mice, suggesting that mutations in developmental transcription factors can provide a sensitized template for adult-onset heart disease. Our findings are the first to link TBX20 mutations to human pathology. They provide insights into how mutation of different genes in an interactive regulatory circuit lead to diverse clinical phenotypes, with implications for diagnosis, genetic screening, and patient follow-up.
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    Journal Title
    American Journal of Human Genetics
    Volume
    81
    Issue
    2
    DOI
    https://doi.org/10.1086/519530
    Subject
    Biological Sciences
    Medical and Health Sciences
    Publication URI
    http://hdl.handle.net/10072/17764
    Collection
    • Journal articles

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