TBX1 loss‑of‑function mutation contributes to congenital conotruncal defects

  • Authors:
    • Min Zhang
    • Fu‑Xing Li
    • Xing‑Yuan Liu
    • Jing‑Yi Hou
    • Shi‑Hong Ni
    • Juan Wang
    • Cui‑Mei Zhao
    • Wei Zhang
    • Ye Kong
    • Ri‑Tai Huang
    • Song Xue
    • Yi‑Qing Yang
  • View Affiliations

  • Published online on: October 24, 2017     https://doi.org/10.3892/etm.2017.5362
  • Pages:447-453
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Abstract

Conotruncal defects (CTDs) account for ~30% of all types of congenital heart disease and contribute to increased morbidity and mortality rates. Increasing evidence suggests that genetic risk factors are involved in the pathogenesis of CTDs. Mutations in a number of genes, including the TBX1 gene that codes for a T‑box transcription factor essential for normal cardiovascular development, may contribute to the development of CTD. CTDs are genetically heterogeneous and the genetic defects responsible for CTDs in the majority of patients remain unknown. The present study sequenced the coding regions and splicing junction boundaries of TBX1 in 136 patients with CTDs and 300 matched healthy individuals. The disease‑causing potential of the identified TBX1 sequence variation was evaluated using MutationTaster, PolyPhen‑2, SIFT and PROVEN software. The functional characteristics of the mutant TBX1 gene were defined using a dual‑luciferase reporter assay system. A novel heterozygous TBX1 mutation, p.S233Y, was identified in a patient with transposition of the great arteries (TGA) and a ventricular septal defect. This mutation was absent in the 300 controls and altered the amino acid produced, serine, which is evolutionarily conserved across several species, and was predicted to be pathogenic in silico. Luciferase assays conducted in COS‑7 cells demonstrated that the newly identified TBX1 mutation was associated with significantly diminished transcriptional activation of the ANF promoter compared with the wild‑type TBX1. To the best of our knowledge, the present study is the first to associate a TBX1 loss‑of‑function mutation with enhanced susceptibility to TGA, which adds significant insight to the molecular mechanism of TGA.

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January 2018
Volume 15 Issue 1

Print ISSN: 1792-0981
Online ISSN:1792-1015

2016 Impact Factor: 1.261
Ranked #50/128 Medicine Research and Experimental
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APA
Zhang, M., Li, F., Liu, X., Hou, J., Ni, S., Wang, J. ... Yang, Y. (2018). TBX1 loss‑of‑function mutation contributes to congenital conotruncal defects. Experimental and Therapeutic Medicine, 15, 447-453. https://doi.org/10.3892/etm.2017.5362
MLA
Zhang, M., Li, F., Liu, X., Hou, J., Ni, S., Wang, J., Zhao, C., Zhang, W., Kong, Y., Huang, R., Xue, S., Yang, Y."TBX1 loss‑of‑function mutation contributes to congenital conotruncal defects". Experimental and Therapeutic Medicine 15.1 (2018): 447-453.
Chicago
Zhang, M., Li, F., Liu, X., Hou, J., Ni, S., Wang, J., Zhao, C., Zhang, W., Kong, Y., Huang, R., Xue, S., Yang, Y."TBX1 loss‑of‑function mutation contributes to congenital conotruncal defects". Experimental and Therapeutic Medicine 15, no. 1 (2018): 447-453. https://doi.org/10.3892/etm.2017.5362