Institut Jacques Monod, Université Paris Diderot, Paris, France.
Hum Mol Genet. 2018 May 1;27(9):1565-1571. doi: 10.1093/hmg/ddy063.
Mitochondrial diseases may be caused by alterations of the mitochondrial genome. The pathogenic variant m.3243A>G is one of the most frequent causes of mitochondrial disease and the most common mitochondrial DNA mutation. Patients with a variant in mitochondrial DNA can have a mixture of mutated and wild-type genomes (heteroplasmy). In the case of the pathogenic variant m.3243A>G, the degree of heteroplasmy (H) correlates to some extent with the severity of the disease. Several longitudinal studies, where H is measured at two different time-points, have shown an annual decline in leukocyte H values. Thus far, only an exponential decay of H with time has been noted but a mechanistic model is lacking. Here, I describe a deterministic mathematical model that accounts for the decline of H in leukocytes based on selective mechanisms acting at the stem cell level. The 'inverted-sigmoid' model provides estimates of at-birth H levels closer to those observed in post-mitotic tissues, such as skeletal muscle, than the estimates provided by an exponential decay. The new model never leads to predictions of H > 100% and provides a stronger correlation between at-birth H values in leukocytes and the scores of the Newcastle Mitochondrial Disease Scale for Adults, which can be of practical utility. This model could be extended to other mitochondrial DNA disease-causing variants.
线粒体疾病可能由线粒体基因组的改变引起。致病变体 m.3243A>G 是线粒体疾病最常见的原因之一，也是最常见的线粒体 DNA 突变。携带线粒体 DNA 变异的患者可能具有突变型和野生型基因组的混合物（异质性）。在致病变体 m.3243A>G 的情况下，异质性（H）的程度在某种程度上与疾病的严重程度相关。几项纵向研究，在两个不同的时间点测量 H，显示白细胞 H 值的年度下降。到目前为止，仅注意到 H 随时间呈指数衰减，但缺乏机制模型。在这里，我描述了一个确定性的数学模型，该模型基于在干细胞水平起作用的选择机制，解释了白细胞中 H 的下降。“倒钟形”模型提供的出生时 H 水平的估计值更接近在有丝分裂后组织（如骨骼肌）中观察到的水平，而不是指数衰减提供的估计值。新模型从未导致 H>100%的预测，并为白细胞中的出生时 H 值与新堡成人线粒体疾病量表的评分之间提供了更强的相关性，这可能具有实际效用。该模型可以扩展到其他线粒体 DNA 致病变体。
