Abstract
Mucopolysaccharidoses (MPS) are a group of diseases caused by mutations resulting in deficiencies of lysosomal enzymes which lead to the accumulation of partially undegraded glycosaminoglycans (GAG). This phenomenon causes severe and chronic disturbances in the functioning of the organism, and leads to premature death. The metabolic defects affect also functions of the brain in most MPS types (except types IV, VI, and IX). The variety of symptoms, as well as the ineffectiveness of GAG-lowering therapies, question the early theory that GAG storage is the only cause of these diseases. As disorders of ion homeostasis increasingly turn out to be co-causes of the pathogenesis of various human diseases, the aim of this work was to determine the perturbations related to the maintenance of the ion balance at both the transcriptome and cellular levels in MPS. Transcriptomic studies, performed with fibroblasts derived from patients with all types/subtypes of MPS, showed extensive changes in the expression of genes involved in processes related to ion binding, transport and homeostasis. Detailed analysis of these data indicated specific changes in the expression of genes coding for proteins participating in the metabolism of Ca2+, Fe2+ and Zn2+. The results of tests carried out with the mouse MPS I model (Idua−/−) showed reductions in concentrations of these 3 ions in the liver and spleen. The results of these studies indicate for the first time ionic concentration disorders as possible factors influencing the course of MPS and show them as hypothetical, additional therapeutic targets for this rare disease.
Highlights
Mucopolysaccharidoses (MPS) are caused by genetic defects in lysosomal enzymes, leading to the accumulation of partially undegraded glycosaminoglycans (GAG) in Depending on the type of MPS, the symptoms of the disease may vary
Transcriptomic studies, indicating disturbances in expression of genes whose products are involved in maintaining ion balance, were performed with fibroblasts collected from patients with all types/subtypes of MPS (MPS I, II, IIIA, IIIB, IIIC, IIID, IVA, IVB, VI, VII, IX) and wild-type fibroblasts (HDFa, Human Dermal Fibroblasts, adults) using the RNA-seq technique
Transcripts involved in ion binding (GO:0043167), ion transport (GO:0006811) and ion homeostasis (GO:0006873) were selected
Summary
Mucopolysaccharidoses (MPS) are caused by genetic defects in lysosomal enzymes, leading to the accumulation of partially undegraded glycosaminoglycans (GAG) in Depending on the type of MPS, the symptoms of the disease may vary. Variability in the disease course is related to the differences in the activity of deficient enzyme (the presence of residual activity or complete inactivity), kind(s) of stored GAG, the efficiency of GAG synthesis 1 3 Vol.:(0123456789) MPS subtype Common name. MPS I MPS II MPS IIIA MPS IIIB MPS IIIC. Scheie, Hurler-Scheie syndrome Hunter syndrome Sanfilippo syndrome Sanfilippo syndrome Sanfilippo syndrome Stored GAG. Sanfilippo syndrome Morquio syndrome Morquio syndrome Maroteaux–Lamy syndrome HS KS, CS KS DS
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