Peng Rui, Li Binbin, Chen Shuxia, Shi Zhiwen, Yu Liwei, Gao Yunqian, Yang Xueyan, Lu Lei, Wang Hongyan
NHC Key Laboratory of Reproduction Regulation, State Key Laboratory of Genetic Engineering, Obstetrics and Gynecology Hospital, Shanghai Institute of Planned Parenthood Research, Institute of Reproduction and Development, Children's Hospital, Fudan University, Shanghai, China.
Shanghai Key Laboratory of Metabolic Remodeling and Health, School of Life Sciences, Institute of Metabolism and Integrative Biology, Fudan University, Shanghai, China.
Front Cardiovasc Med. 2022 Apr 4;9:798033. doi: 10.3389/fcvm.2022.798033. eCollection 2022.
The Glioma-associated oncogene (Gli) family members of zinc finger DNA-binding proteins are core effectors of Sonic hedgehog (SHH) signaling pathway. Studies in model organisms have identified that the genes play critical roles during organ development, including the heart, brain, kidneys, . Deleterious mutations in genes have previously been revealed in several human developmental disorders, but few in congenital heart disease (CHD). In this study, the mutations in genes were captured by next generation sequencing in human cohorts composed of 412 individuals with CHD and 213 ethnically matched normal controls. A total of 20 patient-specific nonsynonymous rare mutations in coding regions of human genes were identified. Functional analyses showed that c.820G> T (p.G274C) is a gain-of-function mutation, while c.878G>A (p.R293H) and c.1442T>A (p.L481X) are loss-of-function mutations. Our findings suggested that deleterious rare mutations in gene broke the balance of the SHH signaling pathway regulation and may constitute a great contribution to human CHD, which shed new light on understanding genetic mechanism of embryo cardiogenesis regulated by SHH signaling.
锌指DNA结合蛋白的胶质瘤相关癌基因（Gli）家族成员是音猬因子（SHH）信号通路的核心效应器。在模式生物中的研究已确定这些基因在包括心脏、大脑、肾脏等器官发育过程中起关键作用。此前在几种人类发育障碍中已发现这些基因的有害突变，但在先天性心脏病（CHD）中发现较少。在本研究中，通过对由412例CHD患者和213例种族匹配的正常对照组成的人类队列进行二代测序，捕获了这些基因的突变。共鉴定出人类这些基因编码区的20个患者特异性非同义罕见突变。功能分析表明，Gli c.820G>T（p.G274C）是一个功能获得性突变，而Gli c.878G>A（p.R293H）和c.1442T>A（p.L481X）是功能丧失性突变。我们的研究结果表明，这些基因中的有害罕见突变打破了SHH信号通路调节的平衡，可能对人类CHD有很大影响，这为理解SHH信号调节胚胎心脏发生的遗传机制提供了新的线索。
