PDF(Pubmed)
Abstract：
Variation in the mitochondrial tRNA Lys gene at position 8296 was previously found to be associated with maternally inherited diabetes mellitus and deafness, hypertrophic cardiomyopathy, myoclonic epilepsy with ragged-red fibers and mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes. The pathogenicity of the m.8296A>G variation is unclear. In this study, we aimed to analyze the mitochondrial proteome in a patient with m.8296A>G variation to elucidate the effects of this mutation at the protein level. Whole-exome sequencing and mitochondrial genome analysis were performed in a patient with sensorineural hearing impairment, cognitive impairment, leukodystrophy, migraine-like headaches, and gastrointestinal dysmotility. Mitochondrial genome analysis identified a homoplasmic m.8296A>G variation in the mitochondrial tRNA Lys gene in the proband and unaffected mother. Global mitochondrial proteome analysis was carried out in the muscle mitochondria of the index patient and a control subject. Comparative muscle mitochondrial proteome analysis revealed a total of 13 nuclear-encoded mitochondrial proteins differently expressed with respect to the control. Ten of the 13 proteins were downregulated. Most of the proteins were involved in ATP synthesis and Krebs cycle and have strong interactions with each other. We considered the m.8296A>G variation to be pathogenic with variable penetrance for our patient\'s phenotype, and this variation led to different expressions of nuclear-encoded proteins involved in energy metabolism.
摘要：
以前发现8296位线粒体tRNALys基因的变异与母系遗传性糖尿病和耳聋有关，肥厚型心肌病,肌阵挛性癫痫伴参差不齐的红纤维和线粒体脑肌病，乳酸性酸中毒,和类似中风的发作。m.8296A>G变异的致病性尚不清楚。在这项研究中,我们旨在分析m.8296A>G变异患者的线粒体蛋白质组,以阐明该突变在蛋白质水平的影响.在患有感觉神经性听力障碍的患者中进行了全外显子组测序和线粒体基因组分析，认知障碍，脑白质营养不良,偏头痛样头痛,和胃肠动力障碍.线粒体基因组分析确定了先证者和未受影响的母亲中线粒体tRNALys基因的同质m.8296A>G变异。在索引患者和对照受试者的肌肉线粒体中进行了全局线粒体蛋白质组分析。比较肌肉线粒体蛋白质组分析显示，与对照相比，总共有13种核编码的线粒体蛋白质表达不同。13种蛋白质中的10种被下调。大多数蛋白质参与ATP合成和Krebs循环，并且彼此之间具有很强的相互作用。我们认为m.8296A>G变异对我们患者的表型具有不同的外显率，这种变化导致参与能量代谢的核编码蛋白的不同表达。
