CITED2 mutation links congenital heart defects to dysregulation of the cardiac gene VEGF and PITX2C expression

Biochem Biophys Res Commun. 2012 Jul 13;423(4):895-9. doi: 10.1016/j.bbrc.2012.06.099. Epub 2012 Jun 23.


CITED2, a cardiac transcription factor, plays an important role in cardiac development. CITED2 mutations lead to a constellation of cardiac defects, which include tetralogy of Fallot and outflow tract malformations. However, the mechanisms underlying these mutations are poorly understood. We investigated the function and mechanism of two missense mutations, G184S and S192G, responsible for tetralogy of Fallot and aortic stenosis, respectively. We found that CITED2 variants decreased its ability to mediate the expression of vascular endothelial growth factor (VEGF) and the expression of the paired-like homeodomain transcription factor 2-gamma (PITX2C), both of which are closely related to cardiac development. Luciferase reporter and mammalian two-hybrid assays showed that G184S and S192G in CITED2 restored the expression of VEGF, which was due to a reduction in its competitiveness with hypoxia inducible factor 1-alpha (HIF1-α) for binding to CBP/p300. In addition, we found that the G184S and S192G mutant decreased cooperation between CITED2 and transcription factor AP2-gamma (TFAP2C) in the transactivation of the PITX2C gene. These results provide important evidence that the mutation of CITED2 may play a role in the development of congenital heart disease (CHD) in humans.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Gene Expression Regulation, Developmental / genetics*
  • HEK293 Cells
  • Heart Defects, Congenital / genetics*
  • Homeodomain Proteins / genetics*
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Mutation, Missense
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism*
  • Trans-Activators / genetics
  • Trans-Activators / metabolism*
  • Transcription Factor AP-2 / metabolism
  • Transcription Factors / genetics*
  • Transcriptional Activation
  • Vascular Endothelial Growth Factor A / genetics*


  • CITED2 protein, human
  • HIF1A protein, human
  • Homeodomain Proteins
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Repressor Proteins
  • TFAP2C protein, human
  • Trans-Activators
  • Transcription Factor AP-2
  • Transcription Factors
  • Vascular Endothelial Growth Factor A
  • homeobox protein PITX2