Variations of CITED2 are associated with congenital heart disease (CHD) in Chinese population

PLoS One. 2014 May 21;9(5):e98157. doi: 10.1371/journal.pone.0098157. eCollection 2014.


CITED2 was identified as a cardiac transcription factor which is essential to the heart development. Cited2-deficient mice showed cardiac malformations, adrenal agenesis and neural crest defects. To explore the potential impact of mutations in CITED2 on congenital heart disease (CHD) in humans, we screened the coding region of CITED2 in a total of 700 Chinese people with congenital heart disease and 250 healthy individuals as controls. We found five potential disease-causing mutations, p.P140S, p.S183L, p.S196G, p.Ser161delAGC and p. Ser192_Gly193delAGCGGC. Two mammalian two-hybrid assays showed that the last four mutations significantly affected the interaction between p300CH1 and CITED2 or HIF1A. Further studies showed that four CITED2 mutations recovered the promoter activity of VEGF by decreasing its competitiveness with HIF1A for binding to p300CH1 and three mutations decreased the consociation of TFAP2C and CITED2 in the transactivation of PITX2C. Both VEGF and PITX2C play very important roles in cardiac development. In conclusion, we demonstrated that CITED2 has a potential causative impact on congenital heart disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Case-Control Studies
  • Child
  • Child, Preschool
  • China
  • Computational Biology
  • DNA Mutational Analysis
  • HEK293 Cells
  • HeLa Cells
  • Heart Defects, Congenital / ethnology
  • Heart Defects, Congenital / genetics*
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics*
  • Infant
  • Molecular Sequence Data
  • Mutagenesis, Site-Directed
  • Mutation
  • Phenotype
  • Promoter Regions, Genetic
  • Repressor Proteins / genetics*
  • Sequence Homology, Amino Acid
  • Trans-Activators / genetics*
  • Two-Hybrid System Techniques
  • Vascular Endothelial Growth Factor A / metabolism


  • CITED2 protein, human
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Repressor Proteins
  • Trans-Activators
  • Vascular Endothelial Growth Factor A

Grant support

This work was supported by the National Basic Research Program of China (2010CB529504), the National Natural Science Foundation of China (81300131) and the Applied Basic Research Program of Qinghai Province (QH2013-z-744). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.