A novel TBX5 loss-of-function mutation associated with sporadic dilated cardiomyopathy

  • Authors:
    • Wei Zhou
    • Lan Zhao
    • Jin‑Qi Jiang
    • Wei‑Feng Jiang
    • Yi‑Qing Yang
    • Xing‑Biao Qiu
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  • Published online on: May 11, 2015     https://doi.org/10.3892/ijmm.2015.2206
  • Pages: 282-288
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Abstract

Dilated cardiomyopathy (DCM) represents the most prevalent form of primary cardiomyopathy, and is the most common reason for heart transplantation and a major cause of congestive heart failure. Aggregating evidence demonstrates that genetic defects are associated with DCM, and a great number of mutations in >50 genes have been linked to DCM. However, DCM is a genetically heterogeneous disorder and the genetic components underpinning DCM in a significant proportion of patients remain unknown. In the present study, the coding exons and flanking exon‑intron boundaries of the T-Box 5 (TBX5) gene, which encodes a T‑box transcription factor required for normal cardiac development, were sequenced in 146 unrelated patients with sporadic DCM. The functional characteristics of the mutant TBX5 were assayed in contrast to its wild‑type counterpart by using a dual‑luciferase reporter assay system. As a result, a novel heterozygous TBX5 mutation, p.A143T, was identified in a patient with sporadic DCM. The missense mutation, which was absent in 400 control chromosomes, altered the amino acid that was completely conserved evolutionarily among species. Biological analyses revealed that the A143T mutation of TBX5 was associated with significantly decreased transcriptional activity on the promoter of the target gene atrial natriuretic factor (ANF), when compared to its wild‑type counterpart. Furthermore, the A143T mutation abolished the synergistic activation of the ANF promoter between TBX5 and GATA binding protein 4 (GATA4), another crucial transcriptional factor for heart development. To the best of our knowledge, this is the first report on the association of a TBX5 loss‑of‑function mutation with an enhanced susceptibility to sporadic DCM, providing novel insight into the molecular mechanisms of the pathogenesis of DCM and suggesting potential implications for the prenatal prophylaxis and personalized treatment of this commonest primary myocardial disease.
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July-2015
Volume 36 Issue 1

Print ISSN: 1107-3756
Online ISSN:1791-244X

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Spandidos Publications style
Zhou W, Zhao L, Jiang JQ, Jiang WF, Yang YQ and Qiu XB: A novel TBX5 loss-of-function mutation associated with sporadic dilated cardiomyopathy. Int J Mol Med 36: 282-288, 2015.
APA
Zhou, W., Zhao, L., Jiang, J., Jiang, W., Yang, Y., & Qiu, X. (2015). A novel TBX5 loss-of-function mutation associated with sporadic dilated cardiomyopathy. International Journal of Molecular Medicine, 36, 282-288. https://doi.org/10.3892/ijmm.2015.2206
MLA
Zhou, W., Zhao, L., Jiang, J., Jiang, W., Yang, Y., Qiu, X."A novel TBX5 loss-of-function mutation associated with sporadic dilated cardiomyopathy". International Journal of Molecular Medicine 36.1 (2015): 282-288.
Chicago
Zhou, W., Zhao, L., Jiang, J., Jiang, W., Yang, Y., Qiu, X."A novel TBX5 loss-of-function mutation associated with sporadic dilated cardiomyopathy". International Journal of Molecular Medicine 36, no. 1 (2015): 282-288. https://doi.org/10.3892/ijmm.2015.2206