共同性外斜视家系的TMC3基因错义突变研究  

Study on missense mutation of TMC3 gene in families with concomitant exotropia

作　　者：高雅 周文涛 李佳迅 李津 史学锋[1] GAO Ya;ZHOU Wentao;LI Jiaxun;LI Jin;SHI Xuefeng(Tianjin Key Laboratory of Ophthalmology and Visual Science,Tianjin Eye Institute,Tianjin Eye Hospital,Clinical College of Ophthalmology,Tianjin Medical University,Tianjin 300020,China;Department of Cell Biology,School of Basic Medical Sciences,Tianjin Medical University,Tianjin 300070,China)

机构地区：[1]天津医科大学眼科临床学院,天津市眼科医院,天津市眼科研究所,天津市眼科学与视觉科学重点实验室,天津300020 [2]天津医科大学基础医学院细胞生物学系,天津300070

出　　处：《天津医科大学学报》2024年第6期543-547,共5页Journal of Tianjin Medical University

基　　金：天津市131创新型人才团队项目(201936);天津市自然科学基金项目(21JCYBJC00780);天津市卫生健康科技项目(TJWJ2023ZD008);天津市医学重点学科(专科)建设项目(TJYXZDXK-016A)。

摘　　要：目的:利用全外显子组测序检测,探讨与共同性外斜视相关的致病突变。方法:招募了2个中国汉族共同性外斜视家系的4例患者以及10名健康人(其中8人为家系外受试者)。2个共同性外斜视家系的先证者均在儿童期被诊断为共同性外斜视,父母中有一方也患有共同性外斜视。提取所有受试者外周血基因组DNA,应用全外显子组测序技术进行变异检测。使用Sanger测序检验得到的变异,通过生物信息学工具预测评估变异的致病性,通过蛋白质结构预测探究突变的作用机制。结果:在2个独立的共同性外斜视家系的4例患者中都检测出了TMC3基因c.1177C>T(p.R1259C)的错义突变,而在所有10名健康受试者中均未发现此突变。该突变表现出与疾病共分离的现象。此外,该突变在2个家系中均通过了Sanger测序验证,并表现为显性遗传模式。该突变位于TMC3的保守区域,对其蛋白质结构的预测发现突变可能通过降低TMC3蛋白的稳定性发挥致病作用。结论:TMC3基因c.1177C>T(p.R1259C)错义突变可能为共同性外斜视新的致病突变。Objective:To identify pathogenic mutations associated with concomitant exotropia with whole exome sequencing.Methods:Four patients with concomitant exotropia from 2 Han Chinese families with concomitant exotropia and 10 healthy subjects(8 of whom were out-of-family subjects)were recruited.The probands of both families were diagnosed with concomitant exotropia in childhood,and one of the parents also had concomitant exotropia.Genomic DNA was extracted from the peripheral blood of all subjects,and whole exome sequencing was applied to detect variants.The variants obtained were examined using Sanger sequencing.Moreover,the pathogenicity of the variants was assessed by predictive bioinformatics tools.The mechanism of action of the mutations was also explored by protein structure prediction.Results:By whole exome sequencing,a missense mutation of the TMC3 gene c.1177C>T(p.R1259C)was detected in 4 patients from 2 independent pedigrees with concomitant exotropia,while this mutation was not found in all 10 healthy subjects.The mutation showed co-segregation with the disease.In addition,the mutation was verified by Sanger sequencing in 2 pedigrees and showed a dominant mode of inheritance.The mutation was located in a conserved region of TMC3,and predictions of its protein structure suggested that the mutation might play a pathogenic role by reducing the stability of the TMC3 protein.Conclusions:A missense mutation c.1177C>T(p.R1259C)of TMC3 gene may be a new causative mutation of concomitant exotropia.

关 键 词：共同性外斜视 TMC3 遗传变异 全外显子组测序 

分 类 号：R77[医药卫生—眼科]