Underestimated aspect of mucopolysaccharidosis pathogenesis: global changes in cellular processes revealed by transcriptomic studies

Lidia Gaffke , Karolina Pierzynowska , Magdalena Podlacha , Dżesika Hoinkis , Estera Rintz , Joanna Brokowska , Zuzanna Cyske , Grzegorz Węgrzyn


Mucopolysaccharidoses (MPS), a group of inherited metabolic disorders caused by deficiency in enzymes involved in degradation of glycosaminoglycans (GAGs), are examples (and models) of monogenic diseases. Accumulation of undegraded GAGs in lysosomes was supposed to be the major cause of MPS symptoms; however, their complexity and variability between particular types of the disease can be hardly explained by such a simple storage mechanism. Here we show that transcriptomic (RNA-seq) analysis of the material derived from fibroblasts of patients suffering from all types and subtypes of MPS, supported by RT-qPCR results, revealed surprisingly large changes in expression of genes involved in various cellular processes, indicating complex mechanisms of MPS. Although each MPS type and subtype was characterized by specific changes in gene expression profile, there were genes with significantly changed expression relative to wild-type cells that could be classified as common for various MPS types, suggesting similar disturbances in cellular processes. Therefore, both common features of all MPS types, and differences between them, might be potentially explained on the basis of changes in certain cellular processes arising from disturbed regulations of genes’ expression. These results may shed a new light on the mechanisms of genetic diseases, indicating how a single mutation can result in complex pathomechanism, due to perturbations in the network of cellular reactions. Moreover, they should be considered in studies on development of novel therapies, suggesting also why currently available treatment methods fail to correct all/most symptoms of MPS. We propose a hypothesis that disturbances in some cellular processes cannot be corrected by simple reduction of GAG levels; thus, combined therapies are necessary which may require improvement of these processes.
Author Lidia Gaffke (FB/DMoB)
Lidia Gaffke,,
- Department of Molecular Biology
, Karolina Pierzynowska (FB/DMoB)
Karolina Pierzynowska,,
- Department of Molecular Biology
, Magdalena Podlacha (FB/DMoB)
Magdalena Podlacha,,
- Department of Molecular Biology
, Dżesika Hoinkis
Dżesika Hoinkis,,
, Estera Rintz (FB/DMoB)
Estera Rintz,,
- Department of Molecular Biology
, Joanna Brokowska (FB/DMoB)
Joanna Brokowska,,
- Department of Molecular Biology
, Zuzanna Cyske (FB/DMoB)
Zuzanna Cyske,,
- Department of Molecular Biology
, Grzegorz Węgrzyn (FB/DMoB)
Grzegorz Węgrzyn,,
- Department of Molecular Biology
Journal seriesInternational Journal of Molecular Sciences, ISSN 1422-0067, (N/A 140 pkt)
Issue year2020
Publication size in sheets0.90
Article number1204
Keywords in Englishmucopolysaccharidoses, transcriptomic analyses, cellular processes
ASJC Classification2700 General Medicine; 1312 Molecular Biology; 1503 Catalysis; 1604 Inorganic Chemistry; 1605 Organic Chemistry; 1606 Physical and Theoretical Chemistry; 1607 Spectroscopy; 1706 Computer Science Applications
URL https://doi.org/10.3390/ijms21041204
Languageen angielski
LicenseJournal (articles only); published final; Uznanie Autorstwa (CC-BY); with publication
Score (nominal)140
Score sourcejournalList
ScoreMinisterial score = 140.0, 08-06-2020, ArticleFromJournal
Publication indicators WoS Citations = 0.000; Scopus SNIP (Source Normalised Impact per Paper): 2018 = 1.224; WoS Impact Factor: 2018 = 4.183 (2) - 2018=4.331 (5)
Citation count*2 (2020-07-21)
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