Development of a human mitochondrial oligonucleotide microarray (h-MitoArray) and gene expression analysis of fibroblast cell lines from 13 patients with isolated F1Fo ATP synthase deficiency.
Development of a human mitochondrial oligonucleotide microarray (h-MitoArray) and gene expression analysis of fibroblast cell lines from 13 patients with isolated F1Fo ATP synthase deficiency.
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DOI：
10.1186/1471-2164-9-38
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发表时间：
2008-01-25
期刊：
影响因子：
4.4
通讯作者：
Kmoch S
中科院分区：
文献类型：
--
作者：
Cízková A;Stránecký V;Ivánek R;Hartmannová H;Nosková L;Piherová L;Tesarová M;Hansíková H;Honzík T;Zeman J;Divina P;Potocká A;Paul J;Sperl W;Mayr JA;Seneca S;Houstĕk J;Kmoch S
为了加强线粒体疾病的研究和鉴别诊断，我们构建并验证了一个寡核苷酸微阵列（h-MitoArray），允许对1632个涉及线粒体生物学、细胞周期调控、信号转导和凋亡的人类基因进行表达分析。使用h-MitoArray，我们分析了9个对照和13个来自F1Fo ATP合成酶缺乏症患者的成纤维细胞系的基因表达谱，这些患者包括2名mt9205ΔTA微缺失患者和11名尚未表征核缺陷的遗传异质性组患者。通过分析基因表达谱，我们试图将患者分为预期缺陷特异性亚组，随后揭示组特异性代偿变化，确定潜在的表型引起途径并确定候选致病基因。分子研究结合无监督聚类方法，确定了患者细胞系的三个亚群- mtDNA突变的M组和核缺陷的N1和N2组。对M组差异表达基因的表达谱和功能注释的比较、基因富集和通路分析显示，M组的转录谱提示线粒体生物发生和G1/S阻滞的同步抑制。N1组复合物I的表达升高，复合物III、V和V型ATP合成酶亚基基因的表达降低，MAPK、Jak-STAT、JNK和p38 MAP激酶通路磷酸化依赖信号相关基因的表达降低，细胞凋亡和氧化应激被激活的迹象与早衰成纤维细胞的表型相似。在N2组中，除了活化的细胞凋亡迹象外，未检测到特异性功能上有意义的变化。个体基因表达谱的评估证实了M组患者中已知的ATP6/ATP8缺陷，并指出了几种导致核缺陷的候选疾病基因。我们的分析表明，ATP合酶蛋白复合物数量的缺乏通常只伴随着ATP合酶相关基因表达的微小变化。这也表明，潜在缺陷的位点（mtDNA vs .核DNA）和严重程度（ATP合酶含量）对细胞基因表达表型有不同的影响，值得进一步研究其他OXPHOS疾病的细胞周期调控和信号转导途径以及相关的药理学模型。
To strengthen research and differential diagnostics of mitochondrial disorders, we constructed and validated an oligonucleotide microarray (h-MitoArray) allowing expression analysis of 1632 human genes involved in mitochondrial biology, cell cycle regulation, signal transduction and apoptosis. Using h-MitoArray we analyzed gene expression profiles in 9 control and 13 fibroblast cell lines from patients with F1Fo ATP synthase deficiency consisting of 2 patients with mt9205ΔTA microdeletion and a genetically heterogeneous group of 11 patients with not yet characterized nuclear defects. Analysing gene expression profiles, we attempted to classify patients into expected defect specific subgroups, and subsequently reveal group specific compensatory changes, identify potential phenotype causing pathways and define candidate disease causing genes. Molecular studies, in combination with unsupervised clustering methods, defined three subgroups of patient cell lines – M group with mtDNA mutation and N1 and N2 groups with nuclear defect. Comparison of expression profiles and functional annotation, gene enrichment and pathway analyses of differentially expressed genes revealed in the M group a transcription profile suggestive of synchronized suppression of mitochondrial biogenesis and G1/S arrest. The N1 group showed elevated expression of complex I and reduced expression of complexes III, V, and V-type ATP synthase subunit genes, reduced expression of genes involved in phosphorylation dependent signaling along MAPK, Jak-STAT, JNK, and p38 MAP kinase pathways, signs of activated apoptosis and oxidative stress resembling phenotype of premature senescent fibroblasts. No specific functionally meaningful changes, except of signs of activated apoptosis, were detected in the N2 group. Evaluation of individual gene expression profiles confirmed already known ATP6/ATP8 defect in patients from the M group and indicated several candidate disease causing genes for nuclear defects. Our analysis showed that deficiency in the ATP synthase protein complex amount is generally accompanied by only minor changes in expression of ATP synthase related genes. It also suggested that the site (mtDNA vs nuclear DNA) and the severity (ATP synthase content) of the underlying defect have diverse effects on cellular gene expression phenotypes, which warrants further investigation of cell cycle regulatory and signal transduction pathways in other OXPHOS disorders and related pharmacological models.
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影响因子：
4
作者：
DiMauro, Salvatore
通讯作者：
DiMauro, Salvatore
DOI：
10.1111/j.2517-6161.1995.tb02031.x
发表时间：
1995-01-01
影响因子：
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