摘要目的:探索线粒体DNA（mitochondrial DNA，mtDNA）变异与早发家族性阿尔茨海默病发病风险的相关性。方法:从2014年3月至2020年4月收集到的早发家族性阿尔茨海默病家系样本中筛选出4个具有母系遗传特征的阿尔茨海默病（Alzheimer′s disease，AD）家系样本，开展mtDNA全序列测序，与修正版的剑桥参考序列比对分析。测序结果根据标准序列记录下每个样本的mtDNA变异位点及相关信息。采用最新版的mtDNA分类系统数据库进行线粒体单倍型类群分类。变异分析方法：根据系统发育树，找出枝端私有变异位点；MitoTool分析变异的保守性；再通过PhyloTree查询突变是否为其他单倍型类群的鉴定变异。通过文献和数据库查询，SIFT致病性预测软件（2015）预测分析。通过I-TASSER 预测蛋白结构，Pymol可视化蛋白结构同源模拟蛋白三级结构分析，分析结构变化。结果:其中一个家系的mtDNA存在稀有非同义变异m.8978T>C，该位点保守系数1.0，致病性分数较高，蛋白结构同源模拟MT-ATP6蛋白三级结构分析，显示该蛋白支链残端的结构改变。结论:mtDNA稀有非同义变异m.8978T>C可能具有潜在的致病性，可能通过线粒体的功能下降影响AD的发病。

abstractsObjectives:To explore the mutations in mitochondrial DNA (mtDNA) and the risk of developing early-onset Alzheimer′s disease(AD).Methods:From March 2014 to April 2020, four pedigrees with maternal inherited characteristics of AD were recruited from the collected pedigree samples of early-onset familial AD. The entire mtDNA sequence was sequenced and compared with the modified Cambridge reference sequence. The latest version of mtDNA classification system database was used to classify mitochondrial haplotypes. Variation analysis method: the phylogenetic tree was used to find out the branch end private variation sites of each family sample proband, the MitoTool was used to analyze the conservatism of variation, and the PhyloTree was used to check whether these mutations were the identification variation of other haplotype groups. The pathogenicity of these variants was predicted by literature and database search, and SIFT pathogenicity prediction (2015). I-TASSER was used to predict the protein structure and Pymol was used to visualize the protein structure homology and to simulate the tertiary protein structure for analysis of the protein structural change.Results:A rare and non-synonymous variation m.8978T>C was detected. The conservative coefficient of this site was 1.0, and the pathogenicity score was high. The tertiary structure of MT-ATP6 protein was simulated by homology analysis, which showed the structural changes of the branched chain residues.Conclusion:Mutation m.8978T>C of mtDNA may have potential pathogenicity and affect the onset of AD through the decline of mitochondrial function.