Bchetnia Mbarka, Tardif Jessica, Morin Charles, Laprise Catherine
Département des sciences fondamentales, Université du Québec à Chicoutimi (UQAC), Saguenay, Canada.
Centre intersectoriel en santé durable (CISD), Université du Québec à Chicoutimi (UQAC), Saguenay, Canada.
Mol Genet Metab Rep. 2022 Feb 5;30:100847. doi: 10.1016/j.ymgmr.2022.100847. eCollection 2022 Mar.
As a result of a founder effect, a Leigh syndrome variant called Leigh syndrome, French-Canadian type (LSFC, MIM / 220,111) is more frequent in Saguenay-Lac-Saint-Jean (SLSJ), a geographically isolated region on northeastern Quebec, Canada. LSFC is a rare autosomal recessive mitochondrial neurodegenerative disorder due to damage in mitochondrial energy production. LSFC is caused by pathogenic variants in the nuclear gene leucine-rich pentatricopeptide repeat-containing (). Despite progress understanding the molecular mode of action of gene, there is no treatment for this disease. The present study aims to identify the biological pathways altered in the LSFC disorder through microarray-based transcriptomic profile analysis of twelve LSFC cell lines compared to twelve healthy ones, followed by gene ontology (GO) and pathway analyses. A set of 84 significantly differentially expressed genes were obtained ( ≥ 0.05; Fold change (Flc) ≥ 1.5). 45 genes were more expressed (53.57%) in LSFC cell lines compared to controls and 39 (46.43%) had lower expression levels. Gene ontology analysis highlighted altered expression of genes involved in the mitochondrial respiratory chain and energy production, glucose and lipids metabolism, oncogenesis, inflammation and immune response, cell growth and apoptosis, transcription, and signal transduction. Considering the metabolic nature of LSFC disease, genes included in the mitochondrial respiratory chain and energy production cluster stood out as the most important ones to be involved in LSFC mitochondrial disorder. In addition, the protein-protein interaction network indicated a strong interaction between the genes included in this cluster. The mitochondrial gene (NADH dehydrogenase [ubiquinone] 1 alpha subcomplex, 4-like 2), with higher expression in LSFC cells, represents a target for functional studies to explain the role of this gene in LSFC disease. This work provides, for the first time, the LSFC gene expression profile in fibroblasts isolated from affected individuals. This represents a valuable resource to understand the pathogenic basis and consequences of dysfunction.
由于奠基者效应，一种名为Leigh综合征，法裔加拿大型（LSFC，MIM / 220,111）的Leigh综合征变体在加拿大魁北克省东北部地理上孤立的地区萨格奈 - 圣让湖地区（SLSJ）更为常见。LSFC是一种罕见的常染色体隐性线粒体神经退行性疾病，由于线粒体能量产生受损所致。LSFC由富含亮氨酸的五肽重复序列核基因中的致病变异引起。尽管在理解该基因的分子作用模式方面取得了进展，但这种疾病仍无治疗方法。本研究旨在通过对12个LSFC细胞系与12个健康细胞系进行基于微阵列的转录组谱分析，随后进行基因本体（GO）和通路分析，来确定LSFC疾病中改变的生物学途径。获得了一组84个显著差异表达的基因（P≤0.05；倍数变化（Flc）≥1.5）。与对照相比，45个基因在LSFC细胞系中表达更高（53.57%），39个（46.43%）表达水平较低。基因本体分析突出了参与线粒体呼吸链和能量产生、葡萄糖和脂质代谢、肿瘤发生、炎症和免疫反应、细胞生长和凋亡、转录以及信号转导的基因表达改变。考虑到LSFC疾病的代谢性质，线粒体呼吸链和能量产生簇中的基因作为参与LSFC线粒体疾病的最重要基因脱颖而出。此外，蛋白质 - 蛋白质相互作用网络表明该簇中包含的基因之间存在强烈相互作用。线粒体基因MT-ND4L（烟酰胺腺嘌呤二核苷酸脱氢酶[泛醌]1α亚复合体，4样2）在LSFC细胞中表达较高，是功能研究的一个靶点，以解释该基因在LSFC疾病中的作用。这项工作首次提供了从受影响个体分离的成纤维细胞中的LSFC基因表达谱。这是理解该基因功能障碍的致病基础和后果的宝贵资源。
