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

Yan Liu; Fengyu Wang; Yuan Wu; Sainan Tan; Qiaolian Wen; Jing Wang; Xiaomei Zhu; Xi Wang; Congmin Li; Xu Ma; Hong Pan

doi:10.1371/journal.pone.0098157

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.

Authors

Yan Liu¹, Fengyu Wang², Yuan Wu³, Sainan Tan⁴, Qiaolian Wen¹, Jing Wang⁵, Xiaomei Zhu¹, Xi Wang¹, Congmin Li², Xu Ma⁶, Hong Pan¹

Affiliations

¹ Graduate School, Peking Union Medical College, Beijing, China; National Research Institute for Family Planning, Beijing, China.
² Henan Research Institute of Population and Family Planning, Key Laboratory of Population Defects Intervention Technology of Henan Province, Zhengzhou, China.
³ Cardiac Surgery Department, Xiamen Heart Center, Organ Transplantation Institute of Xiamen University, Xiang'an District, Xiamen, China.
⁴ Key Laboratory of Genetics and Birth Health of Hunan Province, Family Planning Institute of Hunan Province, Chang sha, China.
⁵ Department of Medical Genetics, School of Basic Medical Sciences, Capital Medical University, Beijing, China.
⁶ Graduate School, Peking Union Medical College, Beijing, China; National Research Institute for Family Planning, Beijing, China; World Health Organization Collaborating Centre for Research in Human Reproduction, Beijing, China.

Abstract

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

Substances

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

Grants and funding

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.