RELT基因移码突变导致遗传性釉质发育不全  

Frameshift mutation in RELT gene causes amelogenesis imperfecta

作　　者：张真伟 徐欣然 高学军[1] 董艳梅[1] 田华[1,3] ZHANG Zhenwei;XU Xinran;GAO Xuejun;DONG Yanmei;TIAN Hua(Department of Cariology and Endodontology,Peking University School and Hospital of Stomatology&National Center for Stomatology&National Clinical Research Center for Oral Diseases&National Engineering Research Center of Oral Biomaterials and Digital Medical Devices,Beijing 100081,China;Department of Conservative Dentistry and Endodontics 2,Shanghai Stomatological Hospital&School of Stomatology,Shanghai Key Laboratory of Craniomaxillofacial Development and Diseases,Fudan University,Shanghai 200001,China;International Clinical Division,Peking University School and Hospital of Stomatology,Beijing 100081,China)

机构地区：[1]北京大学口腔医学院·口腔医院牙体牙髓科,国家口腔医学中心,国家口腔疾病临床医学研究中心,口腔生物材料和数字诊疗装备国家工程研究中心,北京100081 [2]复旦大学附属上海市口腔医院牙体牙髓二科,上海市颅颌面发育与疾病重点实验室,上海200001 [3]北京大学口腔医学院·口腔医院国际门诊部,北京100081

出　　处：《北京大学学报(医学版)》2025年第1期13-18,共6页Journal of Peking University:Health Sciences

基　　金：国家自然科学基金(81300839);北大医学交叉研究种子基金(BMU2022MX019);国家重大疾病多学科合作诊疗能力建设项目北京大学口腔医院牙体牙髓科子课题(PKUSSNMP-201906)。

摘　　要：目的:纳入1例临床特征和遗传方式符合遗传性釉质发育不全的患者家系,在中国人群中发现RELT基因突变与遗传性釉质发育不全相关,分析其突变效应,探究基因型与表型的关系。方法:收集患者及家系成员的临床资料,分析其临床表型;采集家系成员的外周静脉血等生物样本,提取基因组DNA,进行全外显子组测序(whole-exome sequencing,WES),分析其致病基因,采用Sanger测序验证。利用SIFT、PolyPhen-2等网站预测突变的致病性;利用Uniprot网站对比不同物种的蛋白序列,分析蛋白保守性;利用Alphafold 2等生物信息学软件分析突变蛋白在三维结构等方面的改变。结果:先证者表现为典型的钙化不全型遗传性釉质发育不全,磨耗重,釉质较软,表面粗糙着色,部分釉质丧失,其他家系成员不具有类似的口腔表现。WES和Sanger测序结果表明该先证者携带RELT基因的纯合移码突变,即NM_032871.3:c.1169_1170del,其父母均为携带者,该突变被预测为能致病。生物信息学分析结果显示,该突变位点在不同物种间高度保守。蛋白三维结构预测显示,与野生型RELT蛋白相比,突变蛋白p.Pro390fs35构象提前终止,影响该蛋白正常功能。结论:通过对一个遗传性釉质发育不全家系进行表型分析、基因测序及功能预测等,发现RELT基因的纯合移码突变可造成蛋白结构异常,导致钙化不全型遗传性釉质发育不全。Objective:To analyze RELT gene mutation found in a pedigree with clinical features and inheritable pattern consistent with amelogenesis imperfecta(AI)in China,and to study the relationship between its genotype and phenotype.Methods:Clinical and radiological features were recorded for the affected individuals.Peripheral venous blood samples of the patient and family members were collected for further study,and the genomic DNA was extracted to identify the pathogenic gene.Whole exome sequencing(WES)was performed to analyze the possible pathogenic genes,and Sanger sequencing was performed for validation.SIFT and PolyPhen-2 were used to predict and analyze the mutation effect.Comparison of RELT amino acids across different species were performed by using Uniprot website.In addition,the three-dimen-sional structures of the wild type and mutant proteins were predicted by Alphafold 2.Results:The proband exhibited typical hypocalcified AI,with heavy wear,soft enamel,rough and discolored surface,and partial enamel loss,while his parents didn’t have similar manifestations.WES and Sanger sequencing results indicated that the proband carries a homozygous frameshift mutation in RELT gene,NM_032871.3:c.1169_1170del,and both of his parents were carriers.This mutation was predicted to be pathogenic by SIFT and PolyPhen-2.Up to now,there were 11 mutation sites in RELT gene were reported to be associated with AI,and all of the patients exhibited with hypocalcified AI.Compared with the wild-type RELT protein,the mutant protein p.Pro390fs35 conformation terminated prematurely,affecting the normal function of the protein.Conclusion:Through phenotype analysis,gene sequencing,and functional prediction of a Chinese family with typical amelogenesis imperfecta,this study found that RELT gene frameshift mutation can lead to protein dysfunction in AI patients.Further research will focus on the role and mechanism of RELT in enamel development at the molecular and animal levels,providing molecular biology evidence for the genetic counseling

关 键 词：遗传性釉质发育不全 RELT基因 移码突变 釉质矿化 

分 类 号：R781.2[医药卫生—口腔医学]