Del Bo Roberto, Bordoni Andreina, Martinelli Boneschi Filippo, Crimi Marco, Sciacco Monica, Bresolin Nereo, Scarlato Guglielmo, Comi Giacomo Pietri
Department of Neurological Sciences, Centro Dino Ferrari, Padiglione Ponti, University of Milan, IRCCS Ospedale Maggiore Policlinico, 20122, Via F Sforza, 35, 20122 Milan, Italy.
J Neurol Sci. 2002 Oct 15;202(1-2):85-91. doi: 10.1016/s0022-510x(02)00247-2.
The progressive accumulation of mitochondrial DNA (mtDNA) alterations, ranging from single mutations to large-scale deletions, in both the normal ageing process and pathological conditions is a relevant phenomenon in terms of frequency and heteroplasmic degree. Recently, two point mutations (A189G and T408A) within the Displacement loop (D-loop) region, the control region for mtDNA replication, were shown to occur in skeletal muscles from aged individuals. We evaluated the presence and the heteroplasmy levels of these two mutations in muscle biopsies from 91 unrelated individuals of different ages (21 healthy subjects and 70 patients affected by mitochondrial encephalomyopathies). Overall, both mutations significantly accumulate with age. However, a different relationship was discovered among the different subgroups of patients: a higher number of A189G positive subjects younger than 53 years was detected in the subgroup of multiple-deleted patients; furthermore, a trend towards an increased risk for the mutations was evidenced among patients carrying multiple deletions when compared to healthy controls. These findings support the idea that a common biological mechanism determines the accumulation of somatic point mutations in the D-loop region, both in healthy subjects and in mitochondrial myopathy patients. At the same time, it appears that disorders caused by mutations of nuclear genes controlling mtDNA replication (the "mtDNA multiple deletions" syndromes) present a temporal advantage to mutate in the D-loop region. This observation may be relevant to the definition of the molecular pathogenesis of these latter syndromes.
在正常衰老过程和病理状态下，线粒体DNA（mtDNA）改变（从单基因突变到大规模缺失）的逐渐积累，在发生频率和异质性程度方面都是一个相关现象。最近，在mtDNA复制的控制区域——置换环（D-loop）区域内发现的两个点突变（A189G和T408A），出现在老年个体的骨骼肌中。我们评估了来自91名不同年龄的无关个体（21名健康受试者和70名线粒体脑肌病患者）的肌肉活检样本中这两种突变的存在情况和异质性水平。总体而言，这两种突变都随年龄显著积累。然而，在不同亚组的患者中发现了不同的关系：在多重缺失患者亚组中，检测到年龄小于53岁的A189G阳性受试者数量更多；此外，与健康对照相比，携带多重缺失的患者中突变风险增加的趋势得到了证实。这些发现支持了这样一种观点，即一种共同的生物学机制决定了健康受试者和线粒体肌病患者中D-loop区域体细胞点突变的积累。同时，似乎由控制mtDNA复制的核基因突变引起的疾病（“mtDNA多重缺失”综合征）在D-loop区域发生突变具有时间优势。这一观察结果可能与这些后一种综合征的分子发病机制的定义有关。
