Fa Jingjing, Zhang Xiaoqing, Zhang Xiaoping, Qi Ming, Zhang Xingyu, Fu Qihua, Xu Zhuoming, Gao Yunqian, Wang Bo
Pediatric Translational Medicine Institute, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Department of Laboratory Medicine, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Front Cell Dev Biol. 2021 May 10;9:660576. doi: 10.3389/fcell.2021.660576. eCollection 2021.
Congenital heart defects (CHDs) are the most common birth defects worldwide. 22q11.2 deletion syndrome is the most common microdeletion disorder that has been frequently associated with conotruncal malformations. By now, the dosage-sensitive gene has been adopted as the major pathogenic gene responsible for 22q11.2 deletion, which is regulated by canonical Wnt/β-catenin signaling pathway in heart outflow tract development. Here, we report the long noncoding RNA (lncRNA) , which is encompassed in the 22q11.2 region, that can activate canonical Wnt/β-catenin signaling by protecting β-catenin from degradation, which could result from decreased ubiquitination. Such effects were mediated by two short heat shock proteins HSPA6 and α-β-crystallin (CRYAB), whose expression was regulated by through a competing endogenous RNA (ceRNA) mechanism. In clinical practice, the pathogenesis of copy number variation (CNV) was always attributed to haploinsufficiency of protein-coding genes. Here, we report that the 22q11.2 lncRNA significantly activated canonical Wnt/β-catenin signaling, which has major roles in cardiac outflow tract development and should act upstream of . Our results suggested that lncRNAs should contribute to the etiology of CNV-related CHD.
先天性心脏病（CHD）是全球最常见的出生缺陷。22q11.2缺失综合征是最常见的微缺失疾病，常与圆锥动脉干畸形相关。目前，剂量敏感基因已被确定为22q11.2缺失的主要致病基因，该基因在心脏流出道发育过程中受经典Wnt/β-连环蛋白信号通路调控。在此，我们报道了位于22q11.2区域的长链非编码RNA（lncRNA），它可通过保护β-连环蛋白不被降解来激活经典Wnt/β-连环蛋白信号通路，这种保护作用可能是由于泛素化减少所致。这种作用由两种小分子热休克蛋白HSPA6和α-β-晶状体蛋白（CRYAB）介导，它们的表达受lncRNA通过竞争性内源RNA（ceRNA）机制调控。在临床实践中，拷贝数变异（CNV）的发病机制通常归因于蛋白质编码基因的单倍剂量不足。在此，我们报道22q11.2 lncRNA可显著激活经典Wnt/β-连环蛋白信号通路，该信号通路在心脏流出道发育中起主要作用，且应在剂量敏感基因的上游发挥作用。我们的结果表明lncRNAs应参与了CNV相关CHD的病因学过程。
