Bioinformatic analysis of knocking down the Gaucher and Fabry disease causing genes in a well validated primary cell model

Lysosomal storage disorders (LSDs) are a type of inherited metabolic diseases (IMDs) that are caused mostly by deficiencies in the lysosomal enzymes leading to the accumulation of their substrates in cells and organs. Gaucher and Fabry diseases are two types of LSDs that affect the handling of lipid substances (sphingolipids). It is well known that Gaucher disease has a bone phenotype, and recently, studies have found that Fabry disease also affects bone, but this is less well studied. In addition, there are studies focusing on how LSDs affect energy metabolism. This hypothesis generating study aims to identify similarities and differences that may point to common and unique cellular mechanisms of these diseases on bone and identify potential pathways, upstream regulators, and cellular functions that can explain the effect of the diseases on bone and give an insight into any alternative metabolic energy pathways used. The Ingenuity Pathway Analysis (IPA®, QIAGEN Redwood City) software package was used to analyse RNA sequencing data of bone cells where the disease-causing genes for Gaucher and Fabry disease had been knocked down using siRNAs. Key findings reveal the most enriched pathways in Gaucher to be (a) Expression and translocation of olfactory receptors, (b) Keratinization and (c) Hepatic fibrosis. While the most enriched pathways in Fabry are (a) Interferon alpha/beta signalling, (b) Role of hypercytokinemia in the pathogenesis of influenza and (c) OAS antiviral response. The upstream analysis and toxicity list indicate that there are distinct and opposing regulatory pathways between the datasets. Fabry disease is an X-linked disease, with males being more affected. Gender comparisons in Fabry revealed the following pathways, (a) IL-15 production, (b) Colorectal cancer metastasis signalling, (c) Interferon alpha/beta signalling, and (d) Role of hypercytokinemia in the pathogenesis of influenza differing between males and females. The toxicity list which is a prediction of the toxic effects that may result from changes in the gene expression, revealed cardiac hypertrophy as highly significant in the female. Novel upstream regulators that may be involved in influencing disease mechanisms, not previously linked to Fabry or Gaucher disease were identified. In summary, the findings indicate that distinct and overlapping molecular mechanisms and metabolic energy pathways may be involved in Fabry and Gaucher disease, offering a foundation for future studies aimed at understanding the broader implications of lysosomal storage disorders across different cell types and tissues.