Differences in gene expression patterns, revealed by RNA-seq analysis, between various Sanfilippo and Morquio disease subtypes.

Mucopolysaccharidoses (MPS) are genetic disorders that affect up to 1 in 25,000 births. They are caused by dysfunctions of lysosomal hydrolases that degrade glycosaminoglycans (GAGs) which accumulate in cells, damaging their proper functioning. There are 7 types of MPS, distinguished by the kind of accumulated GAG and the defective enzyme, which differ significantly in the course of the disease. Despite the storage of the same GAGs, two of them (MPS III and IV) are divided into subtypes. While the course of MPS IV A and B is similar, the variability between MPS III A, B, C and D is high. This suggests that there are additional aspects that could influence the course of the disease. Therefore, the aim of this study was to determine differences of patterns of gene expression between all MPS III and IV subtypes. Transcriptomic studies, carried out with dermal fibroblasts from patients with all MPS III and IV subtypes, showed a significant variation in the gene expression pattern between individual MPS III subtypes, in contrast to MPS IV. Detailed analysis of transcripts with altered expression levels between MPS III subtypes indicated that these transcripts are mainly involved in maintaining the proper structure of connective tissue (COL4A1, COL4A2, COMP) and the structure of ribosomes (RPL10, RPL23, RPLP2). The results presented in this study indicate a significant role of genetic factors in the diversified course of MPS III subtypes.

Impaired ion homeostasis as a possible associate factor in mucopolysaccharidosis pathogenesis: transcriptomic, cellular and animal studies.

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.

Changes in expressions of genes involved in the regulation of cellular processes in mucopolysaccharidoses as assessed by fibroblast culture-based transcriptomic analyses.

Recent studies indicated that apart from lysosomal storage of glycosaminoglycans (GAGs), secondary and tertiary changes in cellular processes may significantly contribute to development of disorders and symptoms occurring in mucopolysaccharidoses (MPS), a group of lysosomal storage diseases in which neurodegeneration is specific for most types and subtypes. In this report, using transcriptomic data, we demonstrate that regulation of hundreds of genes coding for proteins involved in regulations of various cellular processes is changed in cells derived from patients suffering from all types and subtypes of MPS. Among such genes there are 10 which expression is significantly changed in 9 or more (out of 11) MPS types/subtypes; they include IER3IP1, SAR1A, TMEM38B, PLCB4, SIN3B, ABHD5, SH3BP5, CAPG, PCOLCE2, and MN1. Moreover, there are several genes whose expression is changed over log2 > 4 times in some MPS types relative to control cells. The above analysis indicates that significant changes in expression of genes coding for various regulators of cellular processes may considerably contribute to development of cellular dysfunctions, and further appearance of specific symptoms of MPS, including neurodegeneration.