A novel NKX2.5 loss-of-function mutation responsible for familial atrial fibrillation

  • Authors:
    • Ri-Tai Huang
    • Song Xue
    • Ying-Jia Xu
    • Min Zhou
    • Yi-Qing Yang
  • View Affiliations

  • Published online on: March 22, 2013     https://doi.org/10.3892/ijmm.2013.1316
  • Pages: 1119-1126
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Abstract

Atrial fibrillation (AF) represents the most common form of sustained cardiac arrhythmia and accounts for substantial morbidity and mortality. Increasing evidence demonstrates that abnormal cardiovascular development is involved in the pathogenesis of AF. In this study, the coding exons and splice sites of the NKX2.5 gene, which encodes a homeodomain-containing transcription factor pivotal for normal cardiovascular morphogenesis, were sequenced in 110 unrelated index patients with familial AF. The available relatives of the mutation carrier and 200 unrelated ethnically-matched healthy individuals serving as controls were subsequently genotyped. The disease-causing potential of the identified NKX2.5 variation was predicted by MutationTaster. The functional characteristics of the mutant NKX2.5 protein were analyzed using a dual-luciferase reporter assay system. As a result, a novel heterozygous NKX2.5 mutation, p.F145S, was identified in a family with AF transmitted as an autosomal dominant trait, which co-segregated with AF in the family with complete penetrance. The detected substitution, which altered the amino acid completely conserved evolutionarily across species, was absent in 400 control chromosomes and was automatically predicted to be causative. Functional analysis demonstrated that the NKX2.5 mutant was associated with significantly decreased transcriptional activity compared with its wild-type counterpart. To the best of our knowledge, this is the first report on the association of the NKX2.5 loss-of-function mutation with increased susceptibility to familial AF. The findings of the present study provide novel insights into the molecular mechanism underlying AF, suggesting the potential implications for the early prophylaxis and allele-specific therapy of AF.
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May 2013
Volume 31 Issue 5

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

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Spandidos Publications style
Huang R, Xue S, Xu Y, Zhou M and Yang Y: A novel NKX2.5 loss-of-function mutation responsible for familial atrial fibrillation. Int J Mol Med 31: 1119-1126, 2013
APA
Huang, R., Xue, S., Xu, Y., Zhou, M., & Yang, Y. (2013). A novel NKX2.5 loss-of-function mutation responsible for familial atrial fibrillation. International Journal of Molecular Medicine, 31, 1119-1126. https://doi.org/10.3892/ijmm.2013.1316
MLA
Huang, R., Xue, S., Xu, Y., Zhou, M., Yang, Y."A novel NKX2.5 loss-of-function mutation responsible for familial atrial fibrillation". International Journal of Molecular Medicine 31.5 (2013): 1119-1126.
Chicago
Huang, R., Xue, S., Xu, Y., Zhou, M., Yang, Y."A novel NKX2.5 loss-of-function mutation responsible for familial atrial fibrillation". International Journal of Molecular Medicine 31, no. 5 (2013): 1119-1126. https://doi.org/10.3892/ijmm.2013.1316