携带m.15924A>G突变的Leber遗传性视神经病变线粒体遗传学分析  

Mitochondrial genetic analysis of Leber hereditary optic neuropathy carrying m.15924A>G mutation

作　　者：李文旭 刘贞 陈英琪 张娟娟[1,2] 管敏鑫 Li Wenxu;Liu Zhen;Chen Yingqi;Zhang Juanjuan;Guan Minxin(School of Laboratory Medicine and Life Sciences,Attardi Institute of Mitochondrial Biomedicine,Wenzhou Medical University,Wenzhou 325035,China;Eye Hospital,Wenzhou Medical University,State Key Laboratory of Ophthalmology,Optometry and Vision Science,Wenzhou 325027,China;Institute of Genetics,Zhejiang University,Zhejiang Provincial Key Lab of Genetic and Developmental Disorders,Hangzhou 310058,China)

机构地区：[1]温州医科大学检验医学院(生命科学学院、生物学实验教学中心),Attardi线粒体生物医学研究院,温州325035 [2]温州医科大学附属眼视光医院,省部共建眼视光学和视觉科学国家重点实验室,温州325027 [3]浙江大学遗传学研究所,浙江省遗传缺陷与发育障碍研究重点实验室,杭州310058

出　　处：《国际遗传学杂志》2024年第4期247-257,共11页International Journal of Genetics

基　　金：国家自然科学基金(82071007);浙江省自然科学基金(LY24C060001);温州市基础性医疗卫生科技项目(Y20220152)。

摘　　要：目的对13个携带线粒体tRNA Thr 15924A>G突变Leber遗传性视神经病变(Leber’s hereditary optic neuropathy,LHON)家系进行的线粒体遗传学和功能分析。方法对收集的13个携带m.15924A>G突变家系进行眼科学检查、线粒体全基因组测序、线粒体单体型分析,对照组和突变组细胞进行活性氧和线粒体膜电位分析。结果患者的临床表现及眼科检查均符合LHON的典型特征,平均发病年龄为14.387岁,13个家系平均外显率为14.02%。患者线粒体单体亚型分别为M10、D、C、B、F,分布集中在M、N单体型,其中M单体型占比69.2%,N单体型占30.8%,且携带m.15924A>G突变LHON患者单体型以M、N为主,单体型M发生视力损伤的风险比单体型N大(P=0.027)。m.15924A>G突变破坏了31T-39A碱基对,影响tRNA Thr反密码子臂结构的稳定性,自由能改变。细胞实验结果证明突变组细胞活性氧水平增加(P=0.019),线粒体膜电位水平降低(P<0.001)。结论m.15924A>G突变破坏了tRNA Thr 31T-39A碱基对,自由能改变,细胞活性氧增加,膜电位降低,表明该突变影响tRNA Thr结构的稳定性,导致线粒体功能障碍。ObjectiveTo analyze the mitochondrial haplotype of 13 families carrying mitochondrial tRNA Thr15924A>G mutation of Leber hereditary optic neuropathy(Leber’s hereditary optic neuropathy,LHON).Methods13 m.15924A>G mutant families were examined by ophthalmology,mitochondrial genome sequencing and mitochondrial haplotype analysis.ResultsThe clinical manifestations and ophthalmological examination of the patients were consistent with the typical characteristics of LHON.The mean age of onset was 14.387 years old,and the mean penetrance of the 13 families was 14.02%.The mitochondrial monomer subtypes of the patients were M10,D,C,B,and F,and the distribution was concentrated in M and N haplotypes,among which M haplotypes accounted for 69.2%and N haplotypes accounted for 30.8%.In LHON patients with m.15924A>G mutation,the haplotypes were mainly M and N,and the risk of visual impairment of haplotype M was greater than that of haplotype N(P=0.027).m.15924A>G mutation destroyed 31T-39A base pair,affected the stability of tRNA Thr anti-codon arm structure,and changed the free energy.The results of cell experiment showed that reactive oxygen species increased(P=0.019)and mitochondrial membrane potential decreased(P<0.001)in mutant group.ConclusionThe mutation of m.15924A>G destroys the tRNA Thr31T-39A base pair,changes the free energy,increases the reactive oxygen species,and decreases the membrane potential,indicating that the mutation affects the stability of tRNA Thr structure and leads to mitochondrial dysfunction.

关 键 词：LEBER遗传性视神经病变 m.15924A>G突变 线粒体单体型 线粒体功能障碍 视力损伤 

分 类 号：R774.6[医药卫生—眼科]