Macmillan C, Lach B, Shoubridge E A
Montreal Neurological Institute, PQ, Canada.
Neurology. 1993 Aug;43(8):1586-90. doi: 10.1212/wnl.43.8.1586.
We studied multiple different postmortem tissue samples from a woman and two of her daughters with the MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) tRNA(Leu(UUR)) mutation at nucleotide 3243 in mitochondrial DNA (mtDNA). All tissues examined were heteroplasmic for the mutation. The mean proportion of mutant mtDNAs in the mother's tissues (0.30 +/- 0.10) was significantly lower than that of each of her daughters' (0.76 +/- 0.11, p < 0.03, and 0.72 +/- 0.13, p < 0.001); there was no difference in the fraction of mutant mtDNAs between the daughters (p < 0.71). This difference in the mean proportion of mtDNA mutants between family members correlates with their clinical profiles; the mother had the latest onset of disease and lived longest, while the two daughters had a strikingly similar clinical course. In individual patients, the mean proportion of mutant mtDNAs was not different in tissues deriving from ectodermal, mesodermal, and endodermal germ layers. Variance in the mutant:wild-type mtDNA ratio was normally distributed about the mean, both when all tissues were considered together and when different regions of the CNS were considered separately. Thus, the proportion of mtDNAs carrying the tRNA(Leu(3243)) mutation was not uniform in members of this pedigree and did not undergo rapid mitotic segregation along germ-layer divisions. These findings are consistent with the hypothesis that the overall proportion of mtDNAs carrying this mutation is primarily determined by segregation during oogenesis or early embryologic development and that random replicative (mitotic) segregation, subsequent to the establishment of primary germ layers, is responsible for the variation between tissues.
我们研究了一名女性及其两个女儿的多个不同的死后组织样本，她们都患有线粒体DNA（mtDNA）中核苷酸3243处的MELAS（线粒体脑肌病、乳酸酸中毒和卒中样发作）tRNA（Leu（UUR））突变。所有检测的组织都存在该突变的异质性。母亲组织中突变型mtDNA的平均比例（0.30±0.10）显著低于她的每个女儿（分别为0.76±0.11，p<0.03；0.72±0.13，p<0.001）；两个女儿之间突变型mtDNA的比例没有差异（p<0.71）。家庭成员之间mtDNA突变体平均比例的这种差异与他们的临床特征相关；母亲发病最晚，寿命最长，而两个女儿的临床病程惊人地相似。在个体患者中，来自外胚层、中胚层和内胚层胚层的组织中突变型mtDNA的平均比例没有差异。当将所有组织一起考虑以及分别考虑中枢神经系统的不同区域时，突变型：野生型mtDNA比例的方差均围绕平均值呈正态分布。因此，携带tRNA（Leu（3243））突变的mtDNA比例在这个家系成员中并不均匀，并且没有沿着胚层分裂进行快速的有丝分裂分离。这些发现与以下假设一致，即携带这种突变的mtDNA的总体比例主要由卵子发生或早期胚胎发育过程中的分离决定，并且在初级胚层建立后随机的复制性（有丝分裂）分离是组织间变异的原因。
