论文部分内容阅读
该研究旨在探讨一个非综合征型耳聋(nonsyndromic hearing impairment,NSHI)家系中线粒体t RNAThr 15910C>T和12S r RNA 1555A>G基因突变共同作用对线粒体功能的影响。该研究建立了同时携带线粒体t RNAThr 15910C>T和12S r RNA 1555A>G基因突变(双突变组)、仅携带12S r RNA 1555A>G基因突变(单突变组)和对照组的永生化淋巴细胞,这3组细胞系的线粒体DNA单体型均属于R单体型。对该家系的临床资料进行分析,当包括使用氨基糖苷类抗生素(aminoglycoside antibiotics,Am An)的药物性耳聋家系成员时,此家系耳聋外显率为37.5%;当排除用药的耳聋成员时,耳聋外显率是25.0%;相比之下,在用药和未用药的情况下,已报道的14个m.1555A>G的耳聋家系的平均外显率只有12.8%和6.1%。通过对双突变组、单突变组和对照组永生化细胞系的线粒体功能进行研究,结果发现与对照组相比,双突变和单突变组细胞系的ROS水平分别上升了19.08%(P=0.005 4)和9.05%(P=0.003 7);ΔΨm水平分别下降了47.78%(P=0.006 3)和35.39%(P=0.0245);复合体II活力分别下降了8.26%(P=0.721 1)和19.48%(P=0.004 9),复合体IV活力分别下降了32.75%(P=0.033 5)和27.44%(P=0.180 5)。m.1555A>G与m.15910C>T共同作用,导致ROS生成量升高,ΔΨm水平下降以及线粒体呼吸链复合体IV活力降低等线粒体功能缺陷,提示m.15910C>T可能是m.1555A>G导致耳聋的继发性突变。
The purpose of this study was to investigate the effect of mitochondrial function in mitochondrial function in mitochondrial t RNAThr 15910C> T and 12S r RNA 1555A> G mutations in a nonsyndromic hearing impairment (NSHI) pedigree. In this study, immortalized lymphocytes that harbor both mitochondrial t RNAThr 15910C> T and 12S rRNA 1555A> G mutations (double mutant group) and only 12S rRNA 1555A> G gene mutation (single mutation group) and controls The mitochondrial DNA haplotypes of the three cell lines belong to the R haplotype. Clinical data from this pedigree were analyzed and included a 37.5% deafness pedigree when including deaf individuals with aminoglycoside antibiotics (Am An); deafness The penetrance was 25.0%; in contrast, the average penetrance of 14 m.1555A> G deafness families reported was only 12.8% and 6.1%, both with and without medication. The mitochondrial function of immortalized cell lines in double mutant group, single mutant group and control group was investigated. The results showed that ROS levels in double mutant and single mutant groups increased by 19.08% (P = 0.005 (P = 0.006 3) and 35.39% (P = 0.0245) respectively. The activity of complex II decreased by 8.26% (P = 0.721 1) and 19.48% (P = 0.004 9). The IV activity of complex decreased by 32.75% (P = 0.033 5) and 27.44% (P = 0.180 5), respectively. m.1555A> G interacted with m.15910C> T, resulting in the mitochondrial dysfunction of mitochondria, such as increased ROS generation, decreased ΔΨm and decreased IV activity of mitochondrial respiratory chain complex, suggesting that m.15910C> T may be m.1555A> G Causes secondary deafness mutations.