Underestimated Aspect of Mucopolysaccharidosis Pathogenesis: Global Changes in Cellular Processes Revealed by Transcriptomic Studies

International Journal of Molecular Sciences

Lidia Gaffke¹  Magdalena Podlacha¹  Karolina Pierzynowska¹  Grzegorz Wegrzyn¹  Estera Rintz¹  Joanna Brokowska¹  Zuzanna Cyske¹  Dżesika Hoinkis² 

[1] Department of Molecular Biology, University of Gdansk, Wita Stwosza 59, 80-308 Gdansk, Poland;Intelliseq Ltd., Chabrowa 12/3, Stanisława Konarskiego 42/13, 30-046 Cracow, Poland;

关键词: mucopolysaccharidoses;    transcriptomic analyses;    cellular processes;   

DOI  :  10.3390/ijms21041204

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown