Dysregulation of genes coding for proteins involved in metabolic processes in mucopolysaccharidoses, evidenced by a transcriptomic approach

Abstract

Mucopolysaccharidoses (MPS) are a group of lysosomal storage diseases (LSD) caused by mutations in genes coding for enzymes responsible for degradation of glycosaminoglycans (GAGs). Most types of these severe disorders are characterized by neuronopathic phenotypes. Although lysosomal accumulation of GAGs is the primary metabolic defect in MPS, secondary alterations in biochemical processes are considerable and influence the course of the disease. Early hypothesis suggested that these secondary changes might be due to lysosomal storage-mediated impairment of activities of other enzymes, and subsequent accumulation of various compounds in cells. However, recent studies indicated that expression of hundreds of genes is changed in MPS cells. Therefore, we asked whether metabolic effects observed in MPS are caused primarily by GAG-mediated inhibition of specific biochemical reactions or appear as results of dysregulation of expression of genes coding for proteins involved in metabolic processes. Transcriptomic analyses of 11 types of MPS (using RNA isolated from patient-derived fibroblasts), performed in this study, showed that a battery of the above mentioned genes is dysregulated in MPS cells. Some biochemical pathways might be especially affected by changes in expression of many genes, including GAG metabolism and sphingolipid metabolism which is especially interesting as secondary accumulation of various sphingolipids is one of the best known additional (while significantly enhancing neuropathological effects) metabolic defects in MPS. We conclude that severe metabolic disturbances, observed in MPS cells, can partially arise from changes in the expression of many genes coding for proteins involved in metabolic processes.

Keywords: Mucopolysaccharidoses; Regulation of metabolic processes; Transcriptomics.

Fig. 1

Number of transcripts coding for proteins involved in the cellular metabolic processes (GO:0044237) with changed levels of expression (at FDR < 0.1; p < 0.1) in different types of MPS relative to control cells (HDFa)

Fig. 2

Number of transcripts, corresponding to genes from indicated sub-processes (child processes) of GO:0044237 (cellular metabolic process), defined according to the QuickGO database (cellular biosynthetic process (GO:0044249), regulation of cellular metabolic process (GO:0031323), macromolecule metabolic process (GO:0043170), phosphorus metabolic process (GO:0006793), positive regulation of cellular metabolic process (GO:0031325), negative regulation of cellular metabolic process (GO:0031324), cellular catabolic process (GO:0044248), organic acid metabolic process (GO:0006082), cellular lipid metabolic process (GO:0044255), and generation of precursor metabolites and energy (GO:0006091)), which levels were significantly changed in MPS cells relative to the control cells

Fig. 3

Number of transcripts coding for proteins involved in the metabolic processes of glycosaminoglycans, defined according to the QuickGO database (glycosaminoglycan metabolic process; GO:0030203), glycosaminoglycan biosynthetic process (GO:0006024), mucopolysaccharide metabolic process (GO:1903510), and glycosaminoglycan catabolic process (GO:0006027)) with changed levels of expression (at FDR < 0.1; p < 0.1) in different types of MPS relative to control cells (HDFa)

Fig. 4

Heat map of transcripts coding for proteins involved in metabolic processes which expressions were significantly changed in at least eight MPS types relative to the control (HDFa) cells

Fig. 5

Changes in the sphingolipid metabolism in MPS cells as revealed by levels of expressions of genes coding for proteins involved in this process. The KEGG pathway presents the ‘sphingolipid meabolism’ process, imaged from transcriptomic data derived from MPS cells. Individual proteins or groups of proteins were colored if changes in the expression of indicated genes were observed in at least one type of MPS. Up-regulated and down-regulated genes (and corresponding gene products) are marked in red and blue, respectively. Green-marked boxes indicate results in which no statistically significant differences between MPS and HDFa were determined, and non-marked boxed show those with no transcriptomic results available (no expression in fibroblasts)