A nuclear-mitochondrial DNA interaction affecting hearing impairment in mice
A nuclear-mitochondrial DNA interaction affecting hearing impairment in mice
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DOI：
10.1038/84831
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发表时间：
2001-02-01
期刊：
影响因子：
30.8
通讯作者：
Fischel-Ghodsian, N
中科院分区：
文献类型：
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作者：
Johnson, KR;Zheng, QY;Fischel-Ghodsian, N
线粒体DNA（mtDNA）突变的病理生理学途径和临床表现还没有得到很好的理解。这主要是由于大多数致病性mtDNA突变的异质性以及缺乏临床相关的mtDNA突变动物模型的结果，导致人类听力障碍的mtDNA突变通常是同质的，但一些具有这些突变的个体具有严重的听力损失，而具有相同mtDNA突变的母系亲属具有正常的听力（1，2）。流行病学、生物化学和遗传学数据表明，核基因通常是这些表型差异的主要决定因素（3-5）。为了鉴定母系遗传性听力损失的小鼠模型，我们筛选了具有年龄相关性听力损失（阿勒）的三个近交系小鼠品系A/J、NOD/LtJ和SKH 2/J的相互回交。在（A/JxCAST/Ei）xA/J回交中。与CAST/Ei株mtDNA相比，A/J株mtDNA对听力有显著的不利影响。在（NOD/LtJ xCAST/Ei）xNOD/LtJ和（SKH 2/JxCAST/Ei）xSKH 2/J回交中未观察到这种效应。基因分型显示，这种效应仅见于小鼠10号染色体上阿勒基因座A/J等位基因纯合子的小鼠。在三个近交系的线粒体基因组的测序揭示了一个单核苷酸插入fRNA-Arg基因（mt-Tr）作为线粒体效应的可能介质。这是第一个自然发生的mtDNA突变影响临床表型的小鼠模型，它提供了一个实验模型来解剖mtDNA突变与听力损失之间的病理生理过程。
The pathophysiologic pathways and clinical expression of mitochondrial DNA (mtDNA) mutations are not well understood. This is mainly the result of the heteroplasmic nature of most pathogenic mtDNA mutations and of the absence of clinically relevant animal models with mtDNA mutations, mtDNA mutations predisposing to hearing impairment in humans are generally homoplasmic, yet some individuals with these mutations have severe hearing loss, whereas their maternal relatives with the identical mtDNA mutation have normal hearing(1,2). Epidemiologic, biochemical and genetic data indicate that nuclear genes are often the main determinants of these differences in phenotype(3-5). To identify a mouse model for maternally inherited hearing loss, we screened reciprocal backcrosses of three inbred mouse strains, A/J. NOD/LtJ and SKH2/J, with age-related hearing loss (AHL). In the (A/JxCAST/Ei)xA/J backcross. mtDNA derived from the A/J strain exerted a significant detrimental effect on hearing when compared with mtDNA from the CAST/Ei strain. This effect was not seen in the (NOD/LtJ xCAST/Ei)xNOD/LtJ and (SKH2/JxCAST/Ei)xSKH2/J backcrosses. Genotyping revealed that this effect was seen only in mice homozygous for the A/J allele at the Ahl locus on mouse chromosome 10. Sequencing of the mitochondrial genome in the three inbred strains revealed a single nucleotide insertion in the fRNA-Arg gene (mt-Tr) as the probable mediator of the mitochondrial effect. This is the first mouse model with a naturally occurring mtDNA mutation affecting a clinical phenotype, and it provides an experimental model to dissect the pathophysiologic processes connecting mtDNA mutations to hearing loss.