Abstract
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.
Highlights
Mucopolysaccharidoses (MPS) are a group of inherited metabolic diseases (Zhou et al 2020)
Using transcriptomic data obtained from fibroblasts derived from patients suffering from all types and subtypes of MPS, as well as control fibroblasts, we have analyzed transcripts with significantly changed levels in MPS relative to the control, derived from genes listed in the Ensembl database in the term ‘regulation of cellular process’ (GO:0050794), according to Primary stored GAG(s)a
A Abbreviations: CS chondroitin sulfate, DS dermatan sulfate, HA hyaluronic acid, HS heparan sulfate, KS keratan sulfate, N/A not applicable b When mutations were not determined, the diagnosis of specific MPS type was based on analysis of urinary GAG levels, with indication of kind(s) of GAG(s) with elevated amounts in tested samples, and biochemical determination of deficiency of particular lysosomal enzyme in leukocytes c Catalog numbers are according to cell line description in Coriell Institute
Summary
Mucopolysaccharidoses (MPS) are a group of inherited metabolic diseases (Zhou et al 2020). Very recent transcriptomic analyses indicated that there are hundreds of genes whose transcription is down- or up-regulated in MPS cells relative to control cells (Gaffke et al 2020) These studies were based on the use of lines of fibroblasts derived from patients suffering from all types and subtypes of MPS. Despite obvious limitations of such experiments, like the use of cell types which cannot represent most of tissues in patients’ bodies, and representation of each MPS type/subtype by only one cell lines, the advantages of these studies were possibility to compare transcriptomic changes in all MPS types/subtypes in one experiment and under the same conditions, and possibility to identify genes whose expression is significantly changed in most types/subtypes. It was possible to preliminarily identify the genes whose changed expression in MPS cells might be responsible for or contribute to disorders in
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