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Transcriptomic signatures in Gaucher disease subtypes: A systems biology perspective
Mohammad Elahimanesh1, Reza Ganjali1, Mohammad Najafi1,2
1Clinical Biochemistry Department, Faculty of Medical Sciences, Iran University of Medical Sciences, Tehran, Iran.
Molecular Genetics and Metabolism Reports
|December 1, 2025
Summary
Gaucher disease subtypes show distinct molecular signatures. Transcriptomic analysis reveals unique gene expression patterns in GD1, GD2, and GD3, aiding in targeted diagnostics.
Area of Science:
- Genomics and Molecular Biology
- Lysosomal Storage Disorders
- Transcriptomics
Background:
- Gaucher disease (GD) is a lysosomal storage disorder caused by mutations in the GBA1 gene, leading to glucosylceramidase deficiency.
- GD presents in three main subtypes (GD1, GD2, GD3) with varying severity and clinical manifestations, suggesting distinct underlying molecular mechanisms.
Purpose of the Study:
- To analyze and enrich signaling pathways using transcriptomic profiles from cultured skin fibroblasts of Gaucher disease subtypes (GD1, GD2, GD3).
- To identify differentially expressed genes (DEGs) and construct gene networks for each subtype.
- To discover subtype-specific molecular signatures and potential diagnostic markers for Gaucher disease.
Main Methods:
- Utilized GEO datasets containing transcriptomic profiles of cultured skin fibroblasts from GD1, GD2, and GD3 patients.
- Identified differentially expressed genes (DEGs) using the Limma package in R with adjusted p-value <0.05 and |log2FC| > 1.
- Constructed gene networks using Cytoscape to identify hub genes and enriched pathways, including glyco-sphingolipid metabolism and lysosomal function.
Main Results:
- GD1 showed upregulated genes (e.g., TP53, COL4A1) in mRNA splicing and ECM organization, and downregulated genes (e.g., IL6, TGFBR2) in cytokine and TGF-β signaling.
- GD2 exhibited upregulated interferon-related genes (ISG15, MX1) and MMP1, CXCL8, linked to neuroinflammation and ECM dysregulation.
- GD3 displayed upregulated FOS, AKT1, POSTN, EGR2 in PI3K/AKT and myelination pathways, with downregulated CXCL8 and PTGS2.
Conclusions:
- Distinct molecular signatures were identified for Gaucher disease subtypes, with GD1 characterized by immune and ECM involvement, and GD2/GD3 by neuroinflammation and neurodevelopmental pathways.
- Key hub genes (PSAP, CTSB for GD1; LAMP2, GAA for GD2/GD3) and enriched pathways were highlighted.
- Top DEGs like KDM5D (GD1), MMP1 (GD2), and FOSB (GD3) are proposed as potential subtype-specific markers for targeted diagnostics.
