Isolation and characterization of the putative nuclear modifier gene MTO1 involved in the pathogenesis of deafness-associated mitochondrial 12 S rRNA A1555G mutation
Isolation and characterization of the putative nuclear modifier gene MTO1 involved in the pathogenesis of deafness-associated mitochondrial 12 S rRNA A1555G mutation
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DOI：
10.1074/jbc.m203267200
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发表时间：
2002-07-26
影响因子：
4.8
通讯作者：
Guan, MX
中科院分区：
文献类型：
--
作者：
Li, XM;Li, RH;Guan, MX
已发现人类线粒体12s rRNA A1555G突变与氨基糖苷诱导和非综合征性耳聋有关。然而，已经提出了可能的核修饰基因来调节这种突变的表型表达。在酵母中，编码线粒体蛋白的MTO1突变等位基因只有在与与人类A1555G突变对应的线粒体15s rRNA P-4.4(R)突变偶联时才表现出呼吸缺陷表型。提示mto1样修饰基因可能影响人类A1555G突变的表型表达。在这里，我们报告了全长cDNA的鉴定和人类MTO1同源物的基因组组织的阐明。人类Mto1是一种进化上保守的蛋白，在线粒体tRNA修饰中起作用。分离的人MTO1 cDNA可以补充携带P-454(R)突变的酵母MTO1细胞的呼吸缺陷表型，这一观察结果支持了该蛋白的功能保守性。MTO1在各种组织中普遍表达，但在包括耳蜗在内的高代谢率组织中表达明显升高。这些观察结果表明，人类MTO1在结构和功能上都与酵母MTO1同源。因此，它可能在耳聋相关12s rRNA基因A1555G突变或tRNA基因突变的发病机制中发挥重要作用。
The human mitochondrial 12 S rRNA A1555G mutation has been found to be associated with aminoglycoside-induced and non-syndromic deafness. However, putative nuclear modifier gene(s) have been proposed to regulate the phenotypic expression of this mutation. In yeast, the mutant alleles of MTO1, encoding a mitochondrial protein, manifest respiratory-deficient phenotype only when coupled with the mitochondrial 15 S rRNA P-4.4(R) mutation corresponding to human A1555G mutation. This suggests that the MTO1-like modifier gene may influence the phenotypic expression of human A1555G mutation. Here we report the identification of full-length cDNA and elucidation of genomic organization of the human MTO1 homolog. Human Mto1 is an evolutionarily conserved protein that implicates a role in the mitochondrial tRNA modification. Functional conservation of this protein is supported by the observation that isolated human MTO1 cDNA can complement the respiratory deficient phenotype of yeast mto1 cells carrying P-454(R) mutation. MTO1 is ubiquitously expressed in various tissues, but with a markedly elevated expression in tissues of high metabolic rates including cochlea. These observations suggest that human MTO1 is a structural and functional homolog of yeast MTO1. Thus, it may play an important role in the pathogenesis of deafness-associated A1555G mutation in 12 S rRNA gene or mutations in tRNA genes.