CITED2 Mutations in Conserved Regions Contribute to Conotruncal Heart Defects in Chinese Children
CITED2 Mutations in Conserved Regions Contribute to Conotruncal Heart Defects in Chinese Children
复制标题
CITED2 保守区域的突变导致中国儿童圆锥干心脏缺陷
DOI：
10.1089/dna.2017.3701
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发表时间：
2017
影响因子：
3.1
通讯作者：
Xu Rang
中科院分区：
文献类型：
--
作者：
Li Bojian;Pu Tian;Liu Yang;Xu Yuejuan;Xu Rang
Conotruncal heart defects (CTDs) are severe malformations of outflow tract with heterogeneous morphology. Several missense variants ofCITED2have been identified to cause CTDs in recent researches. In this study, we screened the coding regions ofCITED2in 605 Chinese children with CTDs and found two possible pathogenic mutant sites: p.Q117L and p.T257A, both located in the conserved regions ofCITED2. Then, we investigated the biological and functional alterations of them. Western blotting showed low level of protein expression of mutant Q117 and T257A compared with wild-typeCITED2. Dual-luciferase reporter assay demonstrated that mutant Q117 and T257A decreased the ability ofCITED2to modulate the expression of paired-like homeodomain transcription factor 2 gamma (PITX2C), which are closely related to cardiac growth and left–right patterning. Meanwhile, T257A also exhibited impaired ability to mediate vascular endothelial growth factor expression, another gene closely associated with the normal development of cardiovascular system. Three-dimensional molecular conformation showed reduced hydrogen bond between Asp254 and mutant Thr257, indicating the weakened stability and binding ability ofCITED2. All these results suggest thatCITED2mutations in conserved regions lead to disease-causing biological and functional changes and may contribute to the occurrence of CTDs.
