2个非综合征型先天缺牙家系的MSX1基因突变检测与分析  

Detection and analysis of MSX1 gene mutations in two families with non-syndromic tooth agenesis

作　　者：丁婷婷 刘浩辰 DING Tingting;LIU Haochen(Department of Stomatology,Beijing Children's Hospital,Capital Medical University,National Center for Children's Health,Beijing 100045,China;Department of Prosthodontics,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&Central Laboratory,Beijing 100081,China)

机构地区：[1]国家儿童医学中心首都医科大学附属北京儿童医院口腔科,北京100045 [2]北京大学口腔医学院·口腔医院修复科,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

出　　处：《口腔疾病防治》2025年第5期359-367,共9页Journal of Prevention and Treatment for Stomatological Diseases

基　　金：国家自然科学基金项目(81600851)。

摘　　要：目的对2个非综合征型先天缺牙家系进行突变筛查及分析,为先天缺牙的诊断和治疗提供依据。方法本研究已通过单位医学伦理委员会审查批准,并获得患者知情同意。收集了2个非综合征型先天缺牙核心家系的信息及血液样本,另外收集了100例正常对照的血液样本。通过外显子测序及Sanger测序来探索致病基因突变。使用预测软件Polyphen-2、CADD及fammth分析所发现的突变的致病性。使用Mupro、DU-ET和I-Mutant软件预测突变对蛋白质稳定性的影响。使用保守性分析及蛋白质二维/三维结构分析来预测突变对蛋白质功能的影响。使用DeepLoc 2.1软件预测突变蛋白对亚细胞定位的影响。结果在本研究2个家系中发现了肌节同源异性盒基因1(muscle segment homeobox 1,MSX1)的2个新突变:c.547C>A(p.Gln183Lys)和c.854 T>C(p.Val285Ala)。Polyphen-2、CADD及fammth预测这2个突变存在致病性,ACMG分类这2个突变可能致病。保守性分析显示这2个突变位点(Gln183和Val285)位于进化过程中高度保守区域。蛋白质稳定性预测这2个突变对蛋白质稳定性造成影响。蛋白质二维结构分析显示这2个突变会对蛋白质二维结构造成影响。三维结构分析显示这2个突变造成了三维结构的改变。软件预测这2个突变对蛋白质的亚细胞定位没有影响。结论本研究首次报道了MSX1基因的2个突变(c.547C>A和c.854 T>C)可以导致先天缺牙,为先天缺牙诊断和治疗提供了依据。Objective To screen and analyze mutations in two families with non-syndromic tooth agenesis,providing a theoretical basis for the diagnosis and treatment of tooth agenesis.Methods This study was reviewed and approved by the Medical Ethics Committee,and informed consent was obtained from patients.Information and blood samples from two core families with non-syndromic congenital tooth agenesis were collected,along with blood samples from 100 normal controls.Pathogenic gene mutations were explored through whole exome sequencing and Sanger sequencing.The pathogenicity of the identified mutations was analyzed using prediction software Polyphen-2,CADD,and FAMMTH.The impact of the mutations on protein stability was predicted using Mupro,DUET,and I-Mutant software.Conservation analysis and protein 2D/3D structure analysis were used to predict the impact of mutations on protein function.The impact of the mutant proteins on subcellular localization was predicted using DeepLoc 2.1 software.Results We identified two novel mutations in the muscle segment homeobox 1(MSX1)gene:c.547C>A(p.Gln183Lys)and c.854T>C(p.Val285Ala)in the two families.Polyphen-2,CADD,and FATHMM predicted these mutations to be pathogenic,and ACMG classified these mutations as likely pathogenic.Conservation analysis showed that the two mutation sites(Gln183 and Val285)are located in highly conserved regions during evolution.Protein stability predictions indicated that these mutations influence protein stability.Protein 2D structure analysis indicated that these two mutations affect the 2D structure of the protein.3D structure analysis showed that these two mutations can cause changes in the 3D structure.Software predictions indicated that these mutations do not affect the subcellular localization of the protein.Conclusion This study is the first to report two novel mutations in the MSX1 gene(c.547C>A and c.854T>C)associated with tooth agenesis,providing a basis for clinical diagnosis and treatment of congenital tooth loss.

关 键 词：先天缺牙 基因突变 肌节同源异性盒基因1 遗传病 发育异常 突变筛查 外显子测序 遗传咨询 

分 类 号：R78[医药卫生—口腔医学]