Chinnery P F, Howell N, Lightowlers R N, Turnbull D M
Department of Neurology, The University of Newcastle-upon-Tyne, UK.
Brain. 1998 Oct;121 ( Pt 10):1889-94. doi: 10.1093/brain/121.10.1889.
The majority of pathogenic mitochondrial DNA (mtDNA) mutations are heteroplasmic, with both mutant and wild-type alleles present within the same individual. MtDNA is transmitted only from females to their offspring but a single female can bear offspring who harbour different levels of mutant mtDNA and have a variable phenotype. In single families, this complex genetic and phenotypic variability has confounded the identification of any relationship between the level of mutant mtDNA (mutation load) in the mother and the clinical features of her offspring. To obtain a more accurate description of the inheritance of pathogenic mtDNA mutations, we studied a large number of pedigrees that carried either the mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (A3243G MELAS) or the myoclonic epilepsy with ragged-red fibres (A8344G MERRF) mutations. We made two principal observations. First, for both mutations, higher levels of mutant mtDNA in the mothers' blood were associated with an increased frequency of affected offspring. Secondly, at any one level of maternal mutation load there was a greater frequency of affected offspring for the A3243G MELAS mutation than for the A8344G MERRF mutation. Although these results should not be used to give absolute risks to a female contemplating pregnancy, they suggest that the outcome of pregnancy is related to the level of mutant mtDNA in the mother and that the risks of having affected offspring may differ between different mtDNA mutations.
大多数致病性线粒体DNA（mtDNA）突变是异质性的，同一个体内同时存在突变型和野生型等位基因。mtDNA仅从母亲遗传给后代，但单个母亲所生的后代可能携带不同水平的突变型mtDNA，并且具有可变的表型。在单个家族中，这种复杂的遗传和表型变异性使得难以确定母亲体内突变型mtDNA水平（突变负荷）与后代临床特征之间的任何关系。为了更准确地描述致病性mtDNA突变的遗传情况，我们研究了大量携带线粒体脑肌病伴乳酸酸中毒和卒中样发作（A3243G MELAS）或肌阵挛性癫痫伴破碎红纤维（A8344G MERRF）突变的家系。我们有两个主要发现。第一，对于这两种突变，母亲血液中较高水平的突变型mtDNA与受影响后代的频率增加相关。第二，在任何一个母亲突变负荷水平上，A3243G MELAS突变的受影响后代频率都高于A8344G MERRF突变。虽然这些结果不应被用于给考虑怀孕的女性提供绝对风险，但它们表明怀孕结果与母亲体内突变型mtDNA水平有关，并且不同mtDNA突变导致有受影响后代的风险可能不同。
