先天性室间隔缺损致病基因SOX18新突变的发现及功能研究  

Discovery and functional exploration of a novel SOX18 mutation predisposing to congenital ventricular septal defect

作　　者：徐惠玉 严梓 杨奕清 刘兴元[2] XU Huiyu;YAN Zi;YANG Yiqing;LIU Xingyuan(Department of Pediatrics,Jiading Branch of Shanghai General Hospital,Shanghai Jiao Tong University School of Medicine,Shanghai 201803;Department of Pediatrics,Tongji Hospital,Tongji University School of Medicine,Shanghai 200065;Department of Cardiology,Cardiovascular Research Laboratory,Central Laboratory,Shanghai Fifth People′s Hospital,Fudan University,Shanghai 200240,China)

机构地区：[1]上海市第一人民医院嘉定医院,上海市嘉定区江桥医院儿科,201803 [2]同济大学医学院附属同济医院儿科,200065 [3]复旦大学附属上海市第五人民医院心内科、心血管研究室、中心实验室,200240

出　　处：《国际心血管病杂志》2023年第5期307-312,共6页International Journal of Cardiovascular Disease

基　　金：上海市自然科学基金(16ZR1432500)。

摘　　要：目的:探讨先天性室间隔缺损致病基因SOX18的新突变。方法:收集156例先天性心脏病患儿和216名无先天性心脏病对照者的临床数据和血液样本,提取基因组DNA,测序分析SOX18基因以识别新的致病突变。克隆SOX18基因,构建野生型SOX18表达载体,通过定点诱变产生突变型SOX18表达载体,转染HeLa细胞,应用双报告基因定量分析突变体的功能。结果:在1例散发性先天性室间隔缺损患儿中发现SOX18基因新突变,即NM_018419.3:c.430C>T;p.(Gln144*)突变。该突变不存在于其他先天性心脏病和对照者患儿。双报告基因定量分析表明突变型SOX18对靶基因NR2F2的转录激活作用丧失。结论:SOX18基因功能缺失性突变可能是部分先天性室间隔缺损的分子病因,这对先天性室间隔缺损的的精准防治具有潜在的临床意义。Objective:To explore a novel SOX18 mutation contributing to congenital ventricular septal defect.Methods:In the present investigation,the clinical data and blood samples were collected from 156 children suffering from congenital heart disease and 216 control individuals without congenital heart disease.Genomic DNAs were extracted from the study participants'blood leucocytes.Sequencing analysis of the SOX18 gene was conducted to identify a novel mutation responsible for congenital heart disease.The SOX18 gene was cloned,and its wild-type expression plasmid was constructed.The mutant-type SOX18 expression plasmid was yielded via site-targeted mutagenesis.Hela cells were transiently transfected with various expression plasmids,and the function of the mutant-type SOX18 was quantitatively explored with dual-luciferase reporters.Results:In a child affected with sporadic congenital ventricular septal defect,a novel SOX18 mutation,NM_018419.3:c.430C>T;p.(Gln144*),was discovered,which was absent from the 216 control subjects.Reporter gene assays unveiled that the Gln144*-mutant SOX18 lost the ability to transactivate its target gene NR2F2.Conclusion:SOX18 lossof-function mutation is probably a molecular etiology underpinning congenital ventricular septal defect in a subset of cases,suggesting potential clinical implications for the precise prevention and treatment of congenital ventricular septal defect.

关 键 词：先天性室间隔缺损 遗传学 转录调节 SOX18基因 生化分析 

分 类 号：R725.4[医药卫生—儿科]