GENOTYPE TO PHENOTYPE CORRELATIONS IN MITOCHONDRIAL ENCEPHALOMYOPATHIES ASSOCIATED WITH THE A3243G MUTATION OF MITOCHONDRIAL-DNA
GENOTYPE TO PHENOTYPE CORRELATIONS IN MITOCHONDRIAL ENCEPHALOMYOPATHIES ASSOCIATED WITH THE A3243G MUTATION OF MITOCHONDRIAL-DNA
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DOI：
10.1007/bf00878873
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发表时间：
1995-05-01
影响因子：
6
通讯作者：
ZEVIANI, M
中科院分区：
文献类型：
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作者：
MARIOTTI, C;SAVARESE, N;ZEVIANI, M
我们研究了22名携带人类线粒体DNA（mtDNA）A3243G点突变的受试者。14例患者的临床表型以线粒体脑肌病、乳酸酸中毒和卒中样发作（MELAS）为特征，8例患者为慢性进行性眼外肌麻痹（CPEO）。肌肉中A3243G异质性的比例通过两种方法确定：诊断性限制性片段长度多态性的光密度测定法和固相微型测序法。我们发现A3243G突变的百分比和复合物I的比活性之间存在高度显著的负相关性，复合物I是具有最高数量的mtDNA编码亚基的呼吸复合物，这表明突变对mtDNA翻译的直接影响。未观察到mtDNA突变百分比与是否存在特定临床特征（如中风、眼肌麻痹和糖尿病）之间的相关性。MELAS组mtDNA分子突变率与发病年龄密切相关，而CPEO组mtDNA分子突变率与发病年龄无相关性，提示两组mtDNA分子突变的时间依赖性不同。最后，与其他与破碎红纤维（RRF）相关的mtDNA突变相比，在MELAS（3243）和CPEO（3243）中，我们观察到高比例的RRF对细胞色素c氧化酶的组织化学反应呈阳性，细胞色素c氧化酶的形态学特征似乎是与影响tRNA（Leu（UUR））基因的突变相关的神经肌肉表型的特异性。
We studied 22 subjects carrying the A3243G point mutation of human mitochondrial DNA (mtDNA). In 14 cases the clinical phenotype was characterized by mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS), while 8 patients had chronic progressive external ophthalmoplegia (CPEO). The proportion of A3243G heteroplasmy in muscle was determined by two methods: densitometry on a diagnostic restriction-fragment length polymorphism and solid-phase mini-sequencing. We found a highly significant inverse correlation between the percentage of A3243G mutation and the specific activity of complex I, the respiratory complex with the highest number of mtDNA-encoded subunits, suggesting a direct effect of the mutation on mtDNA translation. No correlation was observed between the percentage of mutated mtDNA and the presence or absence of specific clinical features, such as stroke, ophthalmoplegia and diabetes mellitus. However, in the MELAS group the percentage of mutated mtDNA molecules was strongly cor related with the age of onset, while no such correlation was found in the CPEO group, suggesting a different time-dependent evolution of the mutation in the two groups. Finally, in contrast with other mtDNA mutations associated with ragged-red fibres (RRF), in both MELAS(3243) and CPEO(3243) we observed a high proportion of RRF that were positive to the histochemical reaction to cytochrome c oxidase, a morphological feature that seems to be specific for the neuromuscular phenotypes associated with mutations affecting the tRNA(Leu(UUR)) gene.