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Mitochondrial DNA variants in inclusion body myositis characterized by deep sequencing
Brain Pathology ( IF 5.8 ) Pub Date : 2020-12-22 , DOI: 10.1111/bpa.12931 Carola Hedberg-Oldfors 1 , Ulrika Lindgren 1, 2 , Swaraj Basu 3 , Kittichate Visuttijai 1 , Christopher Lindberg 2 , Maria Falkenberg 3 , Erik Larsson Lekholm 3 , Anders Oldfors 1
Brain Pathology ( IF 5.8 ) Pub Date : 2020-12-22 , DOI: 10.1111/bpa.12931 Carola Hedberg-Oldfors 1 , Ulrika Lindgren 1, 2 , Swaraj Basu 3 , Kittichate Visuttijai 1 , Christopher Lindberg 2 , Maria Falkenberg 3 , Erik Larsson Lekholm 3 , Anders Oldfors 1
Affiliation
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Muscle pathology in inclusion body myositis (IBM) typically includes inflammatory cell infiltration, muscle fibers with rimmed vacuoles and cytochrome c oxidase (COX)-deficient fibers. Previous studies have revealed clonal expansion of large mitochondrial DNA (mtDNA) deletions in the COX-deficient muscle fibers. Technical limitations have prevented complete investigations of the mtDNA deletions and other mtDNA variants. Detailed characterization by deep sequencing of mtDNA in muscle samples from 21 IBM patients and 10 age-matched controls was performed after whole genome sequencing with a mean depth of mtDNA coverage of 46,000x. Multiple large mtDNA deletions and duplications were identified in all IBM and control muscle samples. In general, the IBM muscles demonstrated a larger number of deletions and duplications with a mean heteroplasmy level of 10% (range 1%-35%) compared to controls (1%, range 0.2%-3%). There was also a small increase in the number of somatic single nucleotide variants in IBM muscle. More than 200 rearrangements were recurrent in at least two or more IBM muscles while 26 were found in both IBM and control muscles. The deletions and duplications, with a high recurrence rate, were mainly observed in three mtDNA regions, m.534-4429, m.6330-13993, and m.8636-16072, where some were flanked by repetitive sequences. The mtDNA copy number in IBM muscle was reduced to 42% of controls. Immunohistochemical and western blot analyses of IBM muscle revealed combined complex I and complex IV deficiency affecting the COX-deficient fibers. In conclusion, deep sequencing and quantitation of mtDNA variants revealed that IBM muscles had markedly increased levels of large deletions and duplications, and there were also indications of increased somatic single nucleotide variants and reduced mtDNA copy numbers compared to age-matched controls. The distribution and type of variants were similar in IBM muscle and controls indicating an accelerated aging process in IBM muscle, possibly associated with chronic inflammation.
中文翻译：
以深度测序为特征的包涵体肌炎中的线粒体 DNA 变异
包涵体肌炎 (IBM) 中的肌肉病理学通常包括炎性细胞浸润、具有边缘空泡的肌肉纤维和细胞色素c氧化酶（COX）缺乏的纤维。以前的研究已经揭示了 COX 缺陷肌纤维中大线粒体 DNA (mtDNA) 缺失的克隆扩增。技术限制阻碍了对 mtDNA 缺失和其他 mtDNA 变体的全面调查。在全基因组测序后，通过深度测序来自 21 名 IBM 患者和 10 名年龄匹配的对照的肌肉样本中的 mtDNA 进行详细表征，mtDNA 覆盖的平均深度为 46,000 倍。在所有 IBM 和对照肌肉样本中发现了多个大型 mtDNA 缺失和重复。一般来说，与对照组（1%，范围 0.2%-3%）相比，IBM 肌肉表现出更多的缺失和重复，平均异质性水平为 10%（范围 1%-35%）。IBM 肌肉中体细胞单核苷酸变异的数量也有小幅增加。超过 200 次重排在至少两个或更多 IBM 肌肉中反复出现，而在 IBM 和对照肌肉中发现了 26 次。具有高复发率的缺失和重复主要出现在三个 mtDNA 区域，m.534-4429、m.6330-13993 和 m.8636-16072，其中一些区域两侧有重复序列。IBM 肌肉中的 mtDNA 拷贝数减少到对照组的 42%。IBM 肌肉的免疫组织化学和蛋白质印迹分析显示复合体 I 和复合体 IV 缺乏影响 COX 缺陷纤维。总之，mtDNA 变体的深度测序和定量显示，IBM 肌肉的大缺失和重复水平显着增加，与年龄匹配的对照相比，也有迹象表明体细胞单核苷酸变异增加和 mtDNA 拷贝数减少。IBM 肌肉和对照组中变异的分布和类型相似，表明 IBM 肌肉加速老化过程，可能与慢性炎症有关。
更新日期：2020-12-22
中文翻译：
以深度测序为特征的包涵体肌炎中的线粒体 DNA 变异
包涵体肌炎 (IBM) 中的肌肉病理学通常包括炎性细胞浸润、具有边缘空泡的肌肉纤维和细胞色素c氧化酶（COX）缺乏的纤维。以前的研究已经揭示了 COX 缺陷肌纤维中大线粒体 DNA (mtDNA) 缺失的克隆扩增。技术限制阻碍了对 mtDNA 缺失和其他 mtDNA 变体的全面调查。在全基因组测序后，通过深度测序来自 21 名 IBM 患者和 10 名年龄匹配的对照的肌肉样本中的 mtDNA 进行详细表征，mtDNA 覆盖的平均深度为 46,000 倍。在所有 IBM 和对照肌肉样本中发现了多个大型 mtDNA 缺失和重复。一般来说，与对照组（1%，范围 0.2%-3%）相比，IBM 肌肉表现出更多的缺失和重复，平均异质性水平为 10%（范围 1%-35%）。IBM 肌肉中体细胞单核苷酸变异的数量也有小幅增加。超过 200 次重排在至少两个或更多 IBM 肌肉中反复出现，而在 IBM 和对照肌肉中发现了 26 次。具有高复发率的缺失和重复主要出现在三个 mtDNA 区域，m.534-4429、m.6330-13993 和 m.8636-16072，其中一些区域两侧有重复序列。IBM 肌肉中的 mtDNA 拷贝数减少到对照组的 42%。IBM 肌肉的免疫组织化学和蛋白质印迹分析显示复合体 I 和复合体 IV 缺乏影响 COX 缺陷纤维。总之，mtDNA 变体的深度测序和定量显示，IBM 肌肉的大缺失和重复水平显着增加，与年龄匹配的对照相比，也有迹象表明体细胞单核苷酸变异增加和 mtDNA 拷贝数减少。IBM 肌肉和对照组中变异的分布和类型相似，表明 IBM 肌肉加速老化过程，可能与慢性炎症有关。
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