浙江大学管敏鑫教授X.pptx

浙江大学生命科学学院;线粒体;Mitochondria make a comeback;线粒体疾病 ;Mitochondrial Disorders;人类线粒体蛋白 （1500） ;人类线粒体DNA的分子结构 ;Specific features of mitochondrial genome;A Chinese family with maternally transmitted aminoglycoside-induced and nonsyndromic deafness (Zhao et al. AJHG. 2004);线粒体DNA的阈值效应 ;线粒体DNA的遗传瓶颈;mtDNA基因突变;卡恩斯一塞尔综合征 KSS syndrome;线粒体脑肌病伴乳酸中毒及中风样发作 MERRF-syndrome;线粒体脑肌病伴乳酸中毒及中风样发作（MELAS）;Leber遗传性视神经病 (LHON);耳聋;全球听力障碍人口约有2.8亿 (WHO，) 我国有听力障碍人口2780万， 且每年新增3万多聋儿 (2006年第二次全国残疾人口普查， ) ;耳聋的致病因素;遗传性耳聋及常见致聋基因;浙江大学生命科学学院;发现了氨基糖甙类药物性耳聋母系遗传的规律;Maternally transmitted hearing loss families carrying mitochondrial 12S mutations ;母系遗传药物性耳聋的分子致病机制;基因检测报告单-A1555G突变;降低耳聋发生率;Mutations in Mitochondrial Genome Associated with Human Diseases;总 体 思 路;线粒体12S rRNA A1555G和C1494T 是引起药物性耳聋的主要易感突变;; Function characterization;;Eletrophoretic Patterns of Mitochondrial Translation Products;;Proposed Pathogenic Mechanism of Deafness-Associated 12S rRNA A1555G or C1494 mutation ;核修饰基因增强了A1555G突变相关 的耳聋表型表达;Trmu/Mto2, Mto1, and Mss1/Gtpbp3 are the modifying enzymes for the modification of U34 at tRNALys, tRNAGlu and tRNAGln;Yeast mto2 null mutants expresses a respiratory deficient phenotype only when combined with the 15S rRNA C1409G mutation ;mto2 mutant exhibits defect in 2-thio modifications of the mt tRNAGln, tRNALys, and tRNAGlu, but not cytoplasmic tRNALys (Umeda et al. JBC, 2005);TRMU (MTO2) is the nuclear modifier gene for the phenotypic expression of deafness-associated 12S rRNA mutations;8 European/Israeli deafness pedigrees with the A1555G mutations;A10S mutation located at the N-terminal region of TRMU;The A10S mutation did not affect importing into mitochondria and processing of Trmu processor;TRMU A10S mutation altered mitochondrial tRNA metabolism;Mitochondrial protein labeling analysis;Proposed Pathogenic Mechanism of Deafness-Associated 12S rRNA A1555G or C1494 mutation ;;线粒体DNA继发突变和单体型可增强 A1555G突变的耳聋表型的表达;单体型是相似单倍体的集合，来自同一祖先并具有相同核苷酸突变位点 本项目发现浙