Transcriptomic signatures in Gaucher disease subtypes: A systems biology perspective

Gaucher disease (GD) is a lysosomal storage disorder caused by the failure of <i>GBA1</i> (Glucosylceramidase Beta 1). The aim of study was to analyze and enrich signaling pathways with transcriptomic profiles in cultured skin fibroblasts of GD subtypes (GD1, GD2, GD3) using GEO datasets. Differentially expressed genes (DEGs) were identified using the Limma package in R with a significance threshold (adjusted <i>p</i>-value <0.05 and |log2FC| > 1) and were used in gene networks constructed by Cytoscape. In GD1, up regulated genes (<i>TP53</i>, <i>COL4A1</i>) were found in mRNA splicing and ECM organization, while down regulated genes (<i>IL6</i>, <i>TGFBR2</i>) were linked to cytokine and TGF-β signaling pathways. GD2 showed upregulation of <i>MMP1</i>, <i>CXCL8</i>, and interferon-related genes (<i>ISG15</i>, <i>MX1</i>), associated with interleukin-4/13 signaling and ECM dysregulation, reflecting severe neuroinflammation. GD3 exhibited upregulation of <i>FOS</i>, <i>AKT1</i> (>5 years), and <i>POSTN</i>, <i>EGR2</i> (<5 years), found in PI3K/AKT and myelination signaling pathways, alongside down regulated <i>CXCL8</i> and <i>PTGS2</i> linked to receptor tyrosine kinase signaling pathway. Gene networks identified hub genes (<i>PSAP</i>, <i>CTSB</i> for GD1; <i>LAMP2</i>, <i>GAA</i> for GD2/GD3) and enriched pathways (glycosphingolipid metabolism, lysosomal function). Top 5 % DEGs, including KDM5D (GD1), MMP1 (GD2), and FOSB (GD3), were proposed as subtype-specific markers. The findings highlighted distinct molecular signatures between GD1 (immune/ECM-focused) and GD2/GD3 (neuroinflammatory/neurodevelopmental), informing targeted diagnostics.