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Abstract：
Fabry disease (FD) is an X-linked lysosomal disease caused by an enzyme deficiency of alpha-galactosidase A (α-gal A). This deficiency leads to the accumulation of glycosphingolipids in lysosomes, resulting in a range of clinical symptoms. The complex pathogenesis of FD involves lysosomal dysfunction, altered autophagy, and mitochondrial abnormalities. Omics sciences, particularly transcriptomic analysis, comprehensively understand molecular mechanisms underlying diseases. This study focuses on genome-wide expression analysis in an FD human podocyte model to gain insights into the underlying mechanisms of podocyte dysfunction. Human control and GLA-edited podocytes were used. Gene expression data was generated using RNA-seq analysis, and differentially expressed genes were identified using DESeq2. Principal component analysis and Spearman correlation have explored gene expression trends. Functional enrichment and Reporter metabolite analyses were conducted to identify significantly affected metabolites and metabolic pathways. Differential expression analysis revealed 247 genes with altered expression levels in GLA-edited podocytes compared to control podocytes. Among these genes, 136 were underexpressed, and 111 were overexpressed in GLA-edited cells. Functional analysis of differentially expressed genes showed their involvement in various pathways related to oxidative stress, inflammation, fatty acid metabolism, collagen and extracellular matrix homeostasis, kidney injury, apoptosis, autophagy, and cellular stress response. The study provides insights into molecular mechanisms underlying Fabry podocyte dysfunction. Integrating transcriptomics data with genome-scale metabolic modeling further unveiled metabolic alterations in GLA-edited podocytes. This comprehensive approach contributes to a better understanding of Fabry disease and may lead to identifying new biomarkers and therapeutic targets for this rare lysosomal disorder.
摘要：
法布里病(FD)是由α-半乳糖苷酶A(α-galA)的酶缺乏引起的X连锁溶酶体疾病。这种缺乏导致鞘糖脂在溶酶体中的积累，导致一系列临床症状。FD的复杂发病机制涉及溶酶体功能障碍,自噬改变，和线粒体异常.组学科学，特别是转录组学分析，全面了解疾病的分子机制。这项研究的重点是在FD人足细胞模型中进行全基因组表达分析，以深入了解足细胞功能障碍的潜在机制。使用人对照和GLA编辑的足细胞。使用RNA-seq分析生成基因表达数据，并使用DESeq2鉴定了差异表达的基因。主成分分析和Spearman相关性探讨了基因表达趋势。进行功能富集和报告基因代谢物分析以鉴定显著受影响的代谢物和代谢途径。差异表达分析显示，与对照足细胞相比，GLA编辑的足细胞中的247个基因表达水平发生了变化。在这些基因中,136人被压缩不足，111在GLA编辑的细胞中过表达。差异表达基因的功能分析显示它们参与与氧化应激相关的各种途径,炎症,脂肪酸代谢，胶原蛋白和细胞外基质稳态，肾损伤,凋亡，自噬,和细胞应激反应。该研究提供了对法布里足细胞功能障碍的分子机制的见解。将转录组学数据与基因组规模的代谢建模整合进一步揭示了GLA编辑的足细胞中的代谢改变。这种全面的方法有助于更好地理解法布里病，并可能导致确定这种罕见溶酶体疾病的新生物标志物和治疗靶标。
