Characterization of transcription factor AP-2 β mutations involved in familial isolated patent ductus arteriosus suggests haploinsufficiency
- J Surg Res. 2014 May 15;188(2):466-472. doi: 10.1016/j.jss.2014.01.015.
- 1. Department of Cardiology, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.
- 2. Department of Cardiovascular Medicine, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
- # Contributed equally.
Background: Patent ductus arteriosus (PDA) is one of the most common congenital heart defects. Transcription factor AP-2 beta (TFAP2B) mutations are associated with the Char syndrome, a disorder associated with PDA, and with facial and fingers abnormalities. Recently, we identified two TFAP2B mutations in two families without Char syndrome phenotype, c.601+5G>A and c.435_438delCCGG, and these TFAP2B mutations were associated with familial isolated PDA. The aim of this study was to identify the effects of these mutations on TFAP2B function.
Methods: Plasmids containing the wild-type or mutated TFAP2B were constructed and transfected in cells. Plasmids containing the TFAP2B coactivator, Cpb/p300-interacting transactivator 2 (CITED2), was also transfected. TFAP2B expression was detected by luciferase expression and by Western blot analysis.
Results: These mutations resulted in loss of transactivation function, which could not be improved by Cpb/p300-interacting transactivator 2. The c.601+5G>A mutated gene did not express any protein, whereas the c.435_438delCCGG mutation did not impact the transactivation function activated by the wild-type TFAP2B.
Conclusions: These results suggest that a haploinsufficiency effect of TFAP2B could be involved in familial isolated PDA.