Molecular pathology of MELAS and MERRF - The relationship between mutation load and clinical phenotypes
Molecular pathology of MELAS and MERRF - The relationship between mutation load and clinical phenotypes
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DOI：
10.1093/brain/120.10.1713
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发表时间：
1997-10-01
期刊：
影响因子：
14.5
通讯作者：
Turnbull, DM
中科院分区：
文献类型：
--
作者：
Chinnery, PF;Howell, N;Turnbull, DM
许多遗传性线粒体脑病患者的线粒体DNA （mtDNA）有两种致病突变之一：A3243G或A8344G。携带这些突变的个体在每个细胞中同时携带突变型和野生型等位基因（异质性）。尽管有明确的证据表明体外突变水平与线粒体呼吸链功能之间存在直接关系，但在体内证明临床表型与突变mtDNA水平之间存在明确的相关性更为困难。为了解决这一问题，我们确定了245名携带A3243G或A8344G突变的个体，并研究了特定临床特征的发生率与血液（A3243G, n = 73; A8344G, n = 25）和/或骨骼肌（A3234G, n = III; A8344G, n = 55）突变mtDNA水平之间的关系。在本研究组中，携带A3243G和A8344G突变的个体出现关键临床特征的频率显著不同。对于这两种突变，更常见的临床特征的频率与肌肉中突变mtDNA的水平之间存在相关性。相反，我们没有观察到临床特征的频率与血液中突变mtDNA的水平之间的相关性。因此，测量肌肉中A3243G和A8344G突变水平将有助于识别有发生特定并发症风险的个体，从而改善对携带这些突变的患者及其家属的预后建议。
Many patients with inherited mitochondrial encephalopathies have one of two pathogenic mutations of mitochondrial DNA (mtDNA): A3243G or A8344G. Individuals who harbour these mutations carry both mutant and wild-type alleles within each cell (heteroplasmy). Despite clear evidence of a direct relationship between the level of mutation and mitochondrial respiratory chain function in vitro, it has been more difficult to demonstrate a clear correlation between clinical phenotype and the level of mutant mtDNA in vivo. To address this issue, we identified 245 individuals who carry either the A3243G or A8344G mutations, and studied the relationship between the incidence of specific clinical features and the level of mutant mtDNA in blood (for A3243G, n = 73; for A8344G, n = 25) and/or skeletal muscle (for A3234G, n = III; for A8344G, n = 55). Within this study group, the frequency of key clinical features was significantly different for individuals harbouring the A3243G and A8344G mutations. For both mutations, there was a correlation between the frequency of the more common clinical features and the level of mutant mtDNA in muscle. In contrast, we did not observe a correlation between the frequency of clinical features and the level of mutant mtDNA in blood. Therefore, measurement of the level of the A3243G and A8344G mutations in muscle will allow the identification of individuals who are at risk of developing specific complications, thus improving the prognostic advice that can be given to patients and family members who carry these mutations.