Disclosing the functional changes of two genetic alterations in a patient with Chronic Progressive External Ophthalmoplegia: Report of the novel mtDNA m.7486G>A variant.
Disclosing the functional changes of two genetic alterations in a patient with Chronic Progressive External Ophthalmoplegia: Report of the novel mtDNA m.7486G>A variant.
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DOI：
10.1016/j.nmd.2017.11.006
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发表时间：
2018-04
期刊：
影响因子：
--
通讯作者：
Grazina M
中科院分区：
文献类型：
--
作者：
Bacalhau M;Simões M;Rocha MC;Hardy SA;Vincent AE;Durães J;Macário MC;Santos MJ;Rebelo O;Lopes C;Pratas J;Mendes C;Zuzarte M;Rego AC;Girão H;Wong LC;Taylor RW;Grazina M
在缺失4,977 bp的CPEO患者中发现新的mt-tRNASer（m.7486G>A）变异。位于反密码子环的变异符合致病性标准。这两种遗传缺陷都与肌肉的生化表型分离。检测到MRC复合物的组装损伤。线粒体翻译缺陷和生物能量功能障碍。慢性进行性外眼麻痹（CPEO）以上睑下垂和眼麻痹为特征，通常由线粒体DNA （mtDNA）缺失或mt-tRNA突变引起。本研究的目的是阐明CPEO患者的遗传缺陷，并阐明其潜在的致病机制。这名62岁的女性在12岁时首先出现右眼上睑下垂，随后在45岁时出现左眼上睑下垂，并在55岁时被发现患有外眼肌麻痹。在患者的肌肉中检测到组织病理学异常，包括不规则的红色纤维，缺乏cox的肌肉纤维的马赛克图案以及呼吸链复合物I和IV的联合缺乏。遗传学调查显示患者的肌肉和成纤维细胞中存在“共同缺失”。此外，在肌肉匀浆（50%）、成纤维细胞（11%）和血液（4%）中检测到一种新的异质mt-tRNASer（UCN）变异（m.7486G> a）。单纤维分析显示，这两种基因改变都与缺乏cox的纤维分离。在成纤维细胞中发现了mtdna编码复合物的组装缺陷。功能分析显示明显的生物能量功能障碍，呼吸速率和ATP产生减少以及线粒体去极化。电镜下可见多层小体，提示自噬受到干扰。总之，我们报告了一个CPEO患者有两种可能的遗传来源，都分离与生化和组织化学缺陷。“常见的mtDNA缺失”是最可能的原因，但不能完全排除新型mt-tRNASer（UCN）变体的潜在致病作用。
Novel mt-tRNASer(UCN) (m.7486G>A) variant found in CPEO patient with 4,977 bp deletion. The variant located in the anticodon loop meets the pathogenicity criteria. Both genetic defects segregate with the biochemical phenotype in muscle. Assembly impairment of MRC complexes was detected. Mitochondrial translation defect and bioenergetic dysfunction were revealed. Chronic Progressive External Ophthalmoplegia (CPEO) is characterized by ptosis and ophthalmoplegia and is usually caused by mitochondrial DNA (mtDNA) deletions or mt-tRNA mutations. The aim of the present work was to clarify the genetic defect in a patient presenting with CPEO and elucidate the underlying pathogenic mechanism. This 62-year-old female first developed ptosis of the right eye at the age of 12 and subsequently the left eye at 45 years, and was found to have external ophthalmoplegia at the age of 55 years. Histopathological abnormalities were detected in the patient's muscle, including ragged-red fibres, a mosaic pattern of COX-deficient muscle fibres and combined deficiency of respiratory chain complexes I and IV. Genetic investigation revealed the “common deletion” in the patient's muscle and fibroblasts. Moreover, a novel, heteroplasmic mt-tRNASer(UCN) variant (m.7486G>A) in the anticodon loop was detected in muscle homogenate (50%), fibroblasts (11%) and blood (4%). Single-fibre analysis showed segregation with COX-deficient fibres for both genetic alterations. Assembly defects of mtDNA-encoded complexes were demonstrated in fibroblasts. Functional analyses showed significant bioenergetic dysfunction, reduction in respiration rate and ATP production and mitochondrial depolarization. Multilamellar bodies were detected by electron microscopy, suggesting disturbance in autophagy. In conclusion, we report a CPEO patient with two possible genetic origins, both segregating with biochemical and histochemical defect. The “common mtDNA deletion” is the most likely cause, yet the potential pathogenic effect of a novel mt-tRNASer(UCN) variant cannot be fully excluded.
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DOI：
10.1006/bbrc.1994.2732
发表时间：
1994-11-30
影响因子：
3.1
作者：
LEZZA, AMS;BOFFOLI, D;GADALETA, MN
通讯作者：
GADALETA, MN
影响因子：
11.2
作者：
HOLT, IJ;HARDING, AE;MORGANHUGHES, JA
通讯作者：
MORGANHUGHES, JA
DOI：
10.1007/978-1-61779-504-6_6
发表时间：
2012-01-01
期刊：
MITOCHONDRIAL DISORDERS: BIOCHEMICAL AND MOLECULAR ANALYSIS
影响因子：
--
作者：
Grazina, Manuela M.
通讯作者：
Grazina, Manuela M.
影响因子：
4.4
作者：
Cardaioli, E.;Da Pozzo, P.;Federico, A.
通讯作者：
Federico, A.
影响因子：
64.8
作者：
HOLT, IJ;HARDING, AE;MORGANHUGHES, JA
通讯作者：
MORGANHUGHES, JA