Cytochrome c oxidase deficiency associated with the first stop-codon point mutation in human mtDNA
Cytochrome c oxidase deficiency associated with the first stop-codon point mutation in human mtDNA
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DOI：
10.1086/301910
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发表时间：
1998-07-01
影响因子：
9.8
通讯作者：
Wood, NW
中科院分区：
文献类型：
--
作者：
Hanna, MG;Nelson, IP;Wood, NW
我们已经确定了mtDNA中第一个与人类疾病相关的停止密码子点突变。一名65岁的女性经历了伴有乳酸性酸血症的脑病发作，并伴有运动不耐受和近端肌病。组织化学分析显示，90%的肌纤维表现出细胞色素c氧化酶（COX）活性降低或缺失。生化研究证实了COX活性的严重降低。肌肉免疫细胞化学揭示了cox缺乏纤维中原发性mtDNA缺陷的模式，并与全酶稳定性降低或组装受损相一致。mtDNA的序列分析在患者骨骼肌的9952位置发现了一种新的异质G- > a点突变，而在她的白细胞mtDNA、120名健康对照者或另外60名线粒体疾病患者的mtDNA中未检测到这种突变。这个点突变位于COX亚基III基因的3'端，预计会导致该亚基高度保守的c端区域的最后13个氨基酸的丢失。从患者母亲或其两个儿子的白细胞、骨骼肌或成肌细胞中提取的mtDNA中未检测到该突变，表明该突变不是母体遗传的。单纤维PCR研究为该点突变与COX缺乏症之间的关联提供了直接证据，并表明诱导COX缺乏症所需的突变mtDNA比例低于trna基因点突变所报道的比例。本文报道的研究结果仅是在分子遗传水平上定义的第二例分离性COX缺乏症，并揭示了线粒体疾病的新突变机制。
We have identified the first stop-codon point mutation in mtDNA to be reported in association with human disease. A SG-year-old woman experienced episodes of encephalopathy accompanied by lactic acidemia and had exercise intolerance and proximal myopathy Histochemical analysis showed that 90% of muscle fibers exhibited decreased or absent cytochrome c oxidase (COX) activity. Biochemical studies confirmed a severe isolated reduction in COX activity. Muscle immunocytochemistry revealed a pattern suggestive of a primary mtDNA defect in the COX-deficient fibers and was consistent with either reduced stability or impaired assembly of the holoenzyme. Sequence analysis of mtDNA identified a novel heteroplasmic G-->A point mutation at position 9952 in the patient's skeletal muscle, which was not detected in her leukocyte mtDNA or in that of 120 healthy controls or 60 additional patients with mitochondrial disease. This point mutation is located in the 3' end of the gene for subunit III of COX and is predicted to result in the loss of the last 13 amino acids of the highly conserved C-terminal region of this subunit. It was not detected in mtDNA extracted from leukocytes, skeletal muscle, or myoblasts of the patient's mother or her two sons, indicating that this mutation is not maternally transmitted. Single-fiber PCR studies provided direct evidence for an association between this point mutation and COX deficiency and indicated that the proportion of mutant mtDNA required to induce COX deficiency is lower than that reported for tRNA-gene point mutations. The findings reported here represent only the second case of isolated COX deficiency to be defined at the molecular genetic level and reveal a new mutational mechanism in mitochondrial disease.