A novel NKX2-5 loss-of-function mutation predisposes to familial dilated cardiomyopathy and arrhythmias

  • Authors:
    • Fang Yuan
    • Xing-Biao Qiu
    • Ruo-Gu Li
    • Xin-Kai Qu
    • Juan Wang
    • Ying-Jia Xu
    • Xu Liu
    • Wei-Yi Fang
    • Yi-Qing Yang
    • De-Ning Liao
  • View Affiliations

  • Published online on: December 9, 2014     https://doi.org/10.3892/ijmm.2014.2029
  • Pages: 478-486
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Abstract

Dilated cardiomyopathy (DCM) is the most prevalent type of primary myocardial disease, which is the third most common cause of heart failure and the most frequent reason for heart transplantation. Aggregating evidence demonstrates that genetic risk factors are involved in the pathogenesis of idiopathic DCM. Nevertheless, DCM is of remarkable genetic heterogeneity and the genetic defects underpinning DCM in an overwhelming majority of patients remain unknown. In the present study, the whole coding exons and splice junction sites of the NKX2-5 gene, which encodes a homeodomain transcription factor crucial for cardiac development and structural remodeling, were sequenced in 130 unrelated patients with idiopathic DCM. The available relatives of the index patient harboring an identified mutation and 200 unrelated ethnically matched healthy individuals used as controls were genotyped for the NKX2-5 gene. The functional effect of the mutant NKX2-5 was characterized in contrast to its wild-type counterpart using a dual-luciferase reporter assay system. As a result, a novel heterozygous NKX2-5 mutation, p.S146W, was identified in a family with DCM inherited as an autosomal dominant trait, which co-segregated with DCM in the family with complete penetrance. Notably, the mutation carriers also had arrhythmias, such as paroxysmal atrial fibrillation and atrioventricular block. The missense mutation was absent in 400 reference chromosomes and the altered amino acid was completely conserved evolutionarily among species. Functional analysis revealed that the NKX2-5 mutant was associated with a significantly reduced transcriptional activity. The findings expand the mutational spectrum of NKX2-5 linked to DCM and provide novel insight into the molecular mechanisms underlying DCM, contributing to the antenatal prophylaxis and allele-specific management of DCM.
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February-2015
Volume 35 Issue 2

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

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Spandidos Publications style
Yuan F, Qiu X, Li R, Qu X, Wang J, Xu Y, Liu X, Fang W, Yang Y, Liao D, Liao D, et al: A novel NKX2-5 loss-of-function mutation predisposes to familial dilated cardiomyopathy and arrhythmias. Int J Mol Med 35: 478-486, 2015
APA
Yuan, F., Qiu, X., Li, R., Qu, X., Wang, J., Xu, Y. ... Liao, D. (2015). A novel NKX2-5 loss-of-function mutation predisposes to familial dilated cardiomyopathy and arrhythmias. International Journal of Molecular Medicine, 35, 478-486. https://doi.org/10.3892/ijmm.2014.2029
MLA
Yuan, F., Qiu, X., Li, R., Qu, X., Wang, J., Xu, Y., Liu, X., Fang, W., Yang, Y., Liao, D."A novel NKX2-5 loss-of-function mutation predisposes to familial dilated cardiomyopathy and arrhythmias". International Journal of Molecular Medicine 35.2 (2015): 478-486.
Chicago
Yuan, F., Qiu, X., Li, R., Qu, X., Wang, J., Xu, Y., Liu, X., Fang, W., Yang, Y., Liao, D."A novel NKX2-5 loss-of-function mutation predisposes to familial dilated cardiomyopathy and arrhythmias". International Journal of Molecular Medicine 35, no. 2 (2015): 478-486. https://doi.org/10.3892/ijmm.2014.2029