Gene expression profile in patients with Gaucher disease indicates activation of inflammatory processes

Sci Rep. 2019 Apr 15;9(1):6060. doi: 10.1038/s41598-019-42584-1.

Abstract

Gaucher disease (GD) is a rare inherited metabolic disease caused by pathogenic variants in the GBA1 gene. So far, the pathomechanism of GD was investigated mainly in animal models. In order to delineate the molecular changes in GD cells we analysed gene expression profile in cultured skin fibroblasts from GD patients, control individuals and, additionally, patients with Niemann-Pick type C disease (NPC). We used expression microarrays with subsequent validation by qRT-PCR method. In the comparison GD patients vs. controls, the most pronounced relative fold change (rFC) in expression was observed for genes IL13RA2 and IFI6 (up-regulated) and ATOH8 and CRISPLD2 (down-regulated). Products of up-regulated and down-regulated genes were both enriched in genes associated with immune response. In addition, products of down-regulated genes were associated with cell-to-cell and cell-to-matrix interactions, matrix remodelling, PI3K-Akt signalling pathway and a neuronal survival pathway. Up-regulation of PLAU, IFIT1, TMEM158 and down-regulation of ATOH8 and ISLR distinguished GD patients from both NPC patients and healthy controls. Our results emphasize the inflammatory character of changes occurring in human GD cells indicating that further studies on novel therapeutics for GD should consider anti-inflammatory agents.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Anti-Inflammatory Agents / therapeutic use
  • Biomarkers / metabolism
  • Case-Control Studies
  • Child
  • Child, Preschool
  • Down-Regulation / immunology
  • Female
  • Fibroblasts / immunology
  • Fibroblasts / metabolism*
  • Gaucher Disease / diagnosis
  • Gaucher Disease / drug therapy
  • Gaucher Disease / immunology*
  • Gaucher Disease / metabolism
  • Gene Expression Profiling
  • Glucosylceramidase / deficiency
  • Glucosylceramidase / genetics
  • Healthy Volunteers
  • Humans
  • Infant
  • Infant, Newborn
  • Inflammation / drug therapy
  • Inflammation / immunology
  • Inflammation / metabolism*
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Male
  • Middle Aged
  • Mutation
  • Niemann-Pick C1 Protein
  • Niemann-Pick Disease, Type C / genetics
  • Niemann-Pick Disease, Type C / immunology
  • Niemann-Pick Disease, Type C / metabolism
  • Oligonucleotide Array Sequence Analysis
  • Signal Transduction / immunology*
  • Skin / cytology
  • Up-Regulation / immunology

Substances

  • Anti-Inflammatory Agents
  • Biomarkers
  • Intracellular Signaling Peptides and Proteins
  • NPC1 protein, human
  • Niemann-Pick C1 Protein
  • GBA protein, human
  • Glucosylceramidase