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Article

TBX5 loss-of-function mutation contributes to atrial fibrillation and atypical Holt-Oram syndrome

  • Authors:
    • Dong‑Feng Guo
    • Ruo‑Gu Li
    • Fang Yuan
    • Hong‑Yu Shi
    • Xu‑Min Hou
    • Xin‑Kai Qu
    • Ying‑Jia Xu
    • Min Zhang
    • Xu Liu
    • Jin‑Qi Jiang
    • Yi‑Qing Yang
    • Xing‑Biao Qiu
  • View Affiliations / Copyright

    Affiliations: Department of Emergency Medicine, Shanghai Gongli Hospital, Second Military Medical University, Shanghai 200135, P.R. China, Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, P.R. China, Department of Emergency Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, P.R. China
  • Pages: 4349-4356
    |
    Published online on: March 24, 2016
       https://doi.org/10.3892/mmr.2016.5043
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Abstract

Previous genome-wide association studies have demonstrated that single nucleotide polymorphisms in T‑box (TBX)5 are associated with increased susceptibility to atrial fibrillation (AF), and a recent study has causally linked a TBX5 mutation to atypical Holt-Oram syndrome and paroxysmal AF. However, the prevalence and spectrum of TBX5 mutations in patients with AF remain to be elucidated. In the present study, a cohort of 190 unrelated patients with idiopathic AF were prospectively recruited, with 400 unrelated healthy individuals recruited as controls. The coding exons and flanking introns of the TBX5 gene were sequenced in the participants. The functional characteristics of the mutant TBX5 were delineated in contrast with its wild‑type counterpart using a dual‑luciferase reporter assay system. As a result, a novel heterozygous TBX5 mutation, p.P132S, was identified in an index patient with AF, with a mutational prevalence of ~0.53%. Genetic analysis of the proband's family showed that the mutation co‑segregated with AF, and was transmitted in an autosomal dominant pattern. The missense mutation was absent in the 800 control chromosomes, and the altered amino acid was completely evolutionarily conserved across species. Functional analyses revealed that the mutant TBX5 had significantly reduced transcriptional activity. Furthermore, the mutation markedly decreased the synergistic activation between TBX5 and NK2 homeobox 5, another transcription factor which has been causatively linked to AF. The present study was the first, to the best of our knowledge, to report on the association between a TBX5 loss‑of‑function mutation and increased susceptibility to AF. These results provide novel insight into the molecular mechanism underpinning AF, and have potential implications in the development of novel prophylactic and therapeutic strategies for AF, the most common form of sustained cardiac arrhythmia.
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Copy and paste a formatted citation
Spandidos Publications style
Guo DF, Li RG, Yuan F, Shi HY, Hou XM, Qu XK, Xu YJ, Zhang M, Liu X, Jiang JQ, Jiang JQ, et al: TBX5 loss-of-function mutation contributes to atrial fibrillation and atypical Holt-Oram syndrome. Mol Med Rep 13: 4349-4356, 2016.
APA
Guo, D., Li, R., Yuan, F., Shi, H., Hou, X., Qu, X. ... Qiu, X. (2016). TBX5 loss-of-function mutation contributes to atrial fibrillation and atypical Holt-Oram syndrome. Molecular Medicine Reports, 13, 4349-4356. https://doi.org/10.3892/mmr.2016.5043
MLA
Guo, D., Li, R., Yuan, F., Shi, H., Hou, X., Qu, X., Xu, Y., Zhang, M., Liu, X., Jiang, J., Yang, Y., Qiu, X."TBX5 loss-of-function mutation contributes to atrial fibrillation and atypical Holt-Oram syndrome". Molecular Medicine Reports 13.5 (2016): 4349-4356.
Chicago
Guo, D., Li, R., Yuan, F., Shi, H., Hou, X., Qu, X., Xu, Y., Zhang, M., Liu, X., Jiang, J., Yang, Y., Qiu, X."TBX5 loss-of-function mutation contributes to atrial fibrillation and atypical Holt-Oram syndrome". Molecular Medicine Reports 13, no. 5 (2016): 4349-4356. https://doi.org/10.3892/mmr.2016.5043
Copy and paste a formatted citation
x
Spandidos Publications style
Guo DF, Li RG, Yuan F, Shi HY, Hou XM, Qu XK, Xu YJ, Zhang M, Liu X, Jiang JQ, Jiang JQ, et al: TBX5 loss-of-function mutation contributes to atrial fibrillation and atypical Holt-Oram syndrome. Mol Med Rep 13: 4349-4356, 2016.
APA
Guo, D., Li, R., Yuan, F., Shi, H., Hou, X., Qu, X. ... Qiu, X. (2016). TBX5 loss-of-function mutation contributes to atrial fibrillation and atypical Holt-Oram syndrome. Molecular Medicine Reports, 13, 4349-4356. https://doi.org/10.3892/mmr.2016.5043
MLA
Guo, D., Li, R., Yuan, F., Shi, H., Hou, X., Qu, X., Xu, Y., Zhang, M., Liu, X., Jiang, J., Yang, Y., Qiu, X."TBX5 loss-of-function mutation contributes to atrial fibrillation and atypical Holt-Oram syndrome". Molecular Medicine Reports 13.5 (2016): 4349-4356.
Chicago
Guo, D., Li, R., Yuan, F., Shi, H., Hou, X., Qu, X., Xu, Y., Zhang, M., Liu, X., Jiang, J., Yang, Y., Qiu, X."TBX5 loss-of-function mutation contributes to atrial fibrillation and atypical Holt-Oram syndrome". Molecular Medicine Reports 13, no. 5 (2016): 4349-4356. https://doi.org/10.3892/mmr.2016.5043
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