线粒体tRNA^Phe 593T>C对m.14484T>C相关Leber遗传性视神经病变表型表达的影响  

The mitochondrial tRNA^Phe 593T>C mutation may influence the phenotypic expression of the LHONassociated m.14484T>C mutation

作　　者：徐曼 次晓蕊 吕媛媛 张娟娟[1,3] 管敏鑫 XU Man;CI Xiaorui;LYU Yuanyuan;ZHANG Juanjuan;GUAN Minxin(School of Laboratory Medicine and Life Science,Attardi Institute of Mitochondrial Biomedicine,Wenzhou Medical University,Wenzhou 325035,China;Department of Laboratory Medicine,Ningbo Medical Center Li Huili Hospital,Ningbo 315040,China;Scientific Research Center,Eye Hospital of Wenzhou Medical University,Wenzhou 325027,China)

机构地区：[1]温州医科大学检验医学院生命科学学院Attardi线粒体生物医学研究院,浙江温州325035 [2]宁波医疗中心李惠利医院检验科,浙江宁波315040 [3]温州医科大学附属眼视光医院科研中心,浙江温州325027

出　　处：《温州医科大学学报》2020年第5期356-363,共8页Journal of Wenzhou Medical University

基　　金：国家自然科学基金资助项目(81200724);浙江省医药卫生科技计划项目(2019RC219);温州市基础性科研项目(Y20190067);温州医科大学附属眼视光医院院内创新引导课题(YNCX3201901);浙江省自然科学基金资助项目(LY20C060003).

摘　　要：目的:探讨线粒体tRNA^Phe 593T>C对MT-ND614484T>C相关Leber遗传性视神经病变(LHON)发生发展中的作用。方法:对收集的742例汉族LHON患者和376例对照进行线粒体全基因组测序,并对其中4个LHON家系进行临床、遗传和分子生物学特征评估。结果:4个LHON家系(WZ133、WZ1224、WZ1225和WZ1260)的外显率分别为42.9%、12.5%、12.5%和5.6%,发病年龄9~23岁,平均发病年龄为16岁。线粒体全基因组分析显示WZ133携带m.14484T>C和m.593T>C突变,而其他3个家系仅携带m.593T>C突变。线粒体tRNA二级结构分析发现:m.593T>C突变的tRNA^Phe二级结构发生改变,且自由能增加,使得tRNAPhe结构的稳定性降低,从而导致线粒体功能紊乱。结论:tRNAPhe 593T>C可能对m.14484T>C相关LHOH的表型表达有影响。Objective:To investigate the role of mitochondrial tRNA^Phe 593T>C in the development of Leber’s hereditary optic neuropathy(LHON)-associated with the MT-ND614484T>C mutation.Methods:A cohort of 742 Han Chinese subjects with LHON and 376 control subjects underwent sequence analysis of the complete mitochondrial DNA.4 Chinese families with LHON were evaluated for clinical,genetic and molecular biological characteristics.Results:The penetrance of vision loss in these pedigrees(WZ133,WZ1224,WZ1225 and WZ1260)was 42.9%,12.5%,12.5%and 5.6%,respectively.The age-at-onset of vision impairment in the four families varied from 9 to 23 years.The average age-of-onset was 16.Sequence analysis of mitochondrial genome indicated that WZ133 carried m.14484T>C and m.593T>C,while the other three families only carried m.593T>C.Analysis of the secondary structure of mitochondrial tRNA showed that this mutation resulted in a secondary structure change and higher free energy of tRNA^Phe.The alterations reduced the stability of tRNA^Phe structure and led to mitochondrial dysfunction.Conclusion:The tRNA^Phe 593T>C mutation may have a potential modifier role in the phenotypic manifestation of the primary LHON-associated m.14484T>C mutation.

关 键 词：LEBER遗传性视神经病变 线粒体tRNA^Phe 突变 外显率 中国人群 

分 类 号：R774[医药卫生—眼科]