线粒体DNAT8821G新变异与Leber遗传性视神经病变的相关性  

A novel mutation T8821G in mitochondrial DNA may be associated with Leber＇s hereditary optic neuropathy

作　　者：高敏[1,2] 张赛[1,2] 张增君 赵福新 张娟娟[3] 梁敏[3] 刘晓玲 韦企平[4] 童绎 瞿佳 管敏鑫 

机构地区：[1]浙江省温州医科大学Attardi线粒体生物医学研究院和浙江省医学遗传学重点实验室,325035 [2]附属眼视光学院 [3]浙江大学生命科学学院 [4]北京中医药大学东方医院眼科 [5]福州东南眼科医院

出　　处：《中华医学遗传学杂志》2015年第4期485-489,共5页Chinese Journal of Medical Genetics

基　　金：国家科技支撑计划（2012BA109B03）

摘　　要：目的分析两个Leber遗传性视神经病变（Leber’s hereditary optic neuropathy，LHON）家系的临床和分子遗传学特征，阐明-LHON的分子机制。方法对两例具有典型LHON临床特征的先证者和家系成员进行眼科学及临床检查。对这2个家系的先证者使用24对有部分重叠的引物进行线粒体DNA全序列扩增分析。结果检查发现这两个家系中视力损害的外显率分别为12．5％、30％。经线粒体全基因组测序分析，在ATPase6编码区发现了未报道过的T8821G同质性变异位点。线粒体全序列分析显示两个家系呈现线粒体DNA多态性，均属于东亚单倍型M10a。T8821G变异位于线粒体ATPase6高度保守性区，编码位于ATPase6第3个跨膜区第99位的丝氨酸，可能导致ATPase6的空间结构发生改变，导致合成ATP的功能受损，最终发生视力损伤。结论线粒体ATPase6 T8821G可能是与LHON相关的致病性线粒体基因变异。Objective To report on clinical, genetic and molecular characterization of two Chinese families with Leber＇s hereditary optic neuropathy. Methods Ophthalmological examinations have revealed variable severity and age-at-onset of visual loss among the probands and other matrilineal relatives of both families. The entire mitochondrial genome of the two prohands was amplified with PCR in 24 overlapping fragments using sets of oligonucleotide primers. Results The ophthalmological examinations showed that penetranee was 12. 5~ and 30. 0~ respectively in the two families. Sequence analysis of the complete mitochondrial genomes in these pedigrees has identified unreported homoplasmic T8821G mutation in the ATPase 6 gene and distinct sets of polymorphisms belonging to haplogroups M10a. The T8821G mutation has occurred at the extremely conserved nucleotide （conventional position 99） of the ATPase6. Thus, this mutation may alter structural formation of ATPase6, thereby leading to failure in the synthesis of ATP involved in visual impairment. Conclusion Above observations have suggested that the ATPase6 T8821G mutation may be involved in the pathogenesis of optic neuropathy in these families.

关 键 词：LEBER遗传性视神经病变 线粒体DNA 点突变 视力损伤 变异 

分 类 号：R774.6[医药卫生—眼科]