Multisystem mitochondrial diseases due to mutations in mtDNA-encoded subunits of complex I
Multisystem mitochondrial diseases due to mutations in mtDNA-encoded subunits of complex I
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DOI：
10.1186/s12887-020-1912-x
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发表时间：
2020-01-29
期刊：
影响因子：
2.4
通讯作者：
Tesarova, Marketa
中科院分区：
文献类型：
--
作者：
Danhelovska, Tereza;Kolarova, Hana;Tesarova, Marketa
背景：由于MT-ND基因突变导致的母系遗传性复合物I缺陷是一组异质性的多系统线粒体疾病（MD），预后不良。该研究的目的是表征MT-ND基因突变（包括新型m.13091 T > C变体）对疾病过程的影响，并分析呼吸链复合物的活性、蛋白质亚基的量以及可用肌肉活检和培养的成纤维细胞中的线粒体能量产生系统（MEGS）。方法分光光度法测定呼吸链复合物活性，放射性标记底物法测定MEGS，SDS-PAGE或BN-PAGE法测定肌肉或成纤维细胞蛋白含量。结果在我们的106个携带不同mtDNA突变的无关家系中，我们在来自12个家系的13名MD患者中发现了MT-ND 1、MT-ND 3和MT-ND 5基因的异质性突变，包括新的变异m.13091 T > C。第一个症状发生在儿童早期和青春期之间，并进展为多系统疾病，表现为Leigh或MELAS综合征。MRI显示6例Leigh综合征典型的双侧对称性深灰质受累，3例皮质/白色物质卒中样病变提示MELAS综合征，4例皮质-皮质下病变和灰质受累。MEGS表明所有可用的肌肉样品中的线粒体紊乱，以及成纤维细胞中[1-C-14]丙酮酸的氧化显著降低。分光光度分析显示，在所有的肌肉样品中，除了一个低活性的复合物I和/或复合物I + III，但在成纤维细胞的活动大多是正常的。复合物I活性和mtDNA突变负荷之间没有相关性，但在更严重的患者中通常发现更高水平的异质性。结论在我们地区11%的线粒体疾病家庭中发现了母系遗传的复合体I缺陷。6例患者表现为Leigh，3例表现为MELAS。其余4例患者表现为这两种综合征之间的重叠。MEGS，特别是成纤维细胞中[1-C-14]丙酮酸的氧化可能作为MT-ND突变引起的功能损害的敏感指标。发病早、线粒体DNA异质性高与预后差有关。
Background Maternally inherited complex I deficiencies due to mutations in MT-ND genes represent a heterogeneous group of multisystem mitochondrial disorders (MD) with a unfavourable prognosis. The aim of the study was to characterize the impact of the mutations in MT-ND genes, including the novel m.13091 T > C variant, on the course of the disease, and to analyse the activities of respiratory chain complexes, the amount of protein subunits, and the mitochondrial energy-generating system (MEGS) in available muscle biopsies and cultivated fibroblasts. Methods The respiratory chain complex activities were measured by spectrophotometry, MEGS were analysed using radiolabelled substrates, and protein amount by SDS-PAGE or BN-PAGE in muscle or fibroblasts. Results In our cohort of 106 unrelated families carrying different mtDNA mutations, we found heteroplasmic mutations in the genes MT-ND1, MT-ND3, and MT-ND5, including the novel variant m.13091 T > C, in 13 patients with MD from 12 families. First symptoms developed between early childhood and adolescence and progressed to multisystem disease with a phenotype of Leigh or MELAS syndromes. MRI revealed bilateral symmetrical involvement of deep grey matter typical of Leigh syndrome in 6 children, cortical/white matter stroke-like lesions suggesting MELAS syndrome in 3 patients, and a combination of cortico-subcortical lesions and grey matter involvement in 4 patients. MEGS indicated mitochondrial disturbances in all available muscle samples, as well as a significantly decreased oxidation of [1-C-14] pyruvate in fibroblasts. Spectrophotometric analyses revealed a low activity of complex I and/or complex I + III in all muscle samples except one, but the activities in fibroblasts were mostly normal. No correlation was found between complex I activities and mtDNA mutation load, but higher levels of heteroplasmy were generally found in more severely affected patients. Conclusions Maternally inherited complex I deficiencies were found in 11% of families with mitochondrial diseases in our region. Six patients manifested with Leigh, three with MELAS. The remaining four patients presented with an overlap between these two syndromes. MEGS, especially the oxidation of [1-C-14] pyruvate in fibroblasts might serve as a sensitive indicator of functional impairment due to MT-ND mutations. Early onset of the disease and higher level of mtDNA heteroplasmy were associated with a worse prognosis.