Novel PITX2c loss-of-function mutations associated with complex congenital heart disease

  • Authors:
    • Dong Wei
    • Xiao-Hui Gong
    • Gang Qiu
    • Juan Wang
    • Yi-Qing Yang
  • View Affiliations

  • Published online on: March 7, 2014     https://doi.org/10.3892/ijmm.2014.1689
  • Pages: 1201-1208
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Abstract

Congenital heart disease (CHD) is the most common form of birth defect in humans and is the leading non-infectious cause of infant mortality. Emerging evidence strongly suggests that genetic risk factors play an important role in the pathogenesis of CHD. However, CHD is of pronounced genetic heterogeneity, and the genetic defects responsible for CHD in an overwhelming majority of patients remain unclear. In this study, the entire coding region and splice junction sites of the PITX2c gene, which encodes a paired-like homeodomain transcription factor crucial for proper cardiovascular morphogenesis, was sequenced in 170 unrelated neonates with CHD. The available relatives of the mutation carriers and 200 unrelated ethnically matched healthy individuals were genotyped. The disease-causing potential of the PITX2c sequence variations was predicted by MutationTaster and PolyPhen-2. The functional effect of the mutations was characterized using a luciferase reporter assay system. As a result, 2 novel heterozygous PITX2c mutations, p.R91Q and p.T129S, were identified in 2 unrelated newborns with transposition of the great arteries and ventricular septal defect, respectively. A genetic scan of the pedigrees revealed that each mutation co-segregated with CHD transmitted in an autosomal dominant pattern with complete penetrance. The mutations, which altered the amino acids completely conserved evolutionarily, were absent in 400 normal chromosomes and were predicted to be causative. Functional analysis revealed that the PITX2c mutations were both associated with significantly diminished transcriptional activity compared with their wild-type counterpart. This study demonstrates the association between PITX2c loss-of-function mutations and the transposition of the great arteries and ventricular septal defect in humans, providing further insight into the molecular mechanisms responsible for CHD.
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May-2014
Volume 33 Issue 5

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

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Spandidos Publications style
Wei D, Gong X, Qiu G, Wang J and Yang Y: Novel PITX2c loss-of-function mutations associated with complex congenital heart disease. Int J Mol Med 33: 1201-1208, 2014
APA
Wei, D., Gong, X., Qiu, G., Wang, J., & Yang, Y. (2014). Novel PITX2c loss-of-function mutations associated with complex congenital heart disease. International Journal of Molecular Medicine, 33, 1201-1208. https://doi.org/10.3892/ijmm.2014.1689
MLA
Wei, D., Gong, X., Qiu, G., Wang, J., Yang, Y."Novel PITX2c loss-of-function mutations associated with complex congenital heart disease". International Journal of Molecular Medicine 33.5 (2014): 1201-1208.
Chicago
Wei, D., Gong, X., Qiu, G., Wang, J., Yang, Y."Novel PITX2c loss-of-function mutations associated with complex congenital heart disease". International Journal of Molecular Medicine 33, no. 5 (2014): 1201-1208. https://doi.org/10.3892/ijmm.2014.1689