A novel mitochondrial tRNAGlu (MTTE) gene mutation causing chronic progressive external ophthalmoplegia at low levels of heteroplasmy in muscle
A novel mitochondrial tRNAGlu (MTTE) gene mutation causing chronic progressive external ophthalmoplegia at low levels of heteroplasmy in muscle
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DOI：
10.1016/j.jns.2010.08.014
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发表时间：
2010-11-15
影响因子：
4.4
通讯作者：
Taylor, Robert W.
中科院分区：
文献类型：
--
作者：
Alston, Charlotte L.;Lowe, James;Taylor, Robert W.
线粒体呼吸链缺陷与成人和儿童的不同临床表型相关，可能由核或线粒体DNA（mtDNA）突变引起。我们报告的慢性进行性眼外肌麻痹（CPEO）和肌病患者的分子遗传学研究，肌肉活检采取11年分开显示细胞色素c氧化酶（考克斯）缺乏纤维的比例逐步增加。早期活检的线粒体遗传学分析似乎排除了mtDNA重排和mtDNA点突变。然而，在第二次活检中对来自单个COX缺陷肌纤维的mtDNA进行测序，发现了线粒体tRNA（Glu）（MTTE）基因内未报告的m.14723 T>C取代，这符合致病性的所有标准。m.14723 T>C突变在包括肌肉在内的几种组织中均不存在，这表明这是一个新生事件，而对第一次肌肉活检的定量分析证实了非常低水平的突变（7%突变的mtDNA），这突出了一个潜在的问题，即致病性mtDNA突变可能仍然无法使用已建立的筛查方法检测到。(C)2010 Elsevier B.V.保留所有权利。
Mitochondrial respiratory chain defects are associated with diverse clinical phenotypes in both adults and children, and may be caused by mutations in either nuclear or mitochondrial DNA (mtDNA). We report the molecular genetic investigations of a patient with chronic progressive external ophthalmoplegia (CPEO) and myopathy where muscle biopsies taken 11 years apart revealed a progressive increase in the proportion of cytochrome c oxidase (COX)-deficient fibres. Mitochondrial genetic analysis of the early biopsy had seemingly excluded both mtDNA rearrangements and mtDNA point mutations. Sequencing mtDNA from individual COX-deficient muscle fibres in the second biopsy, however, identified an unreported m.14723 T>C substitution within the mitochondrial tRNA(Glu) (MTTE) gene, which fulfilled all canonical criteria for pathogenicity. The m.14723 T>C mutation was absent from several tissues, including muscle, from maternal relatives suggesting a de novo event, whilst quantitative analysis of the first muscle biopsy confirmed a very low level of the mutation (7% mutated mtDNA), highlighting a potential problem whereby pathogenic mtDNA mutations may remain undetected using established screening methodologies. (C) 2010 Elsevier B.V. All rights reserved.