Abstract
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.
Highlights
Each of about 10,000 monogenic diseases, described to date [1], is caused by mutations in a single gene, symptoms of the vast majority of them are complex
We found that a number of transcripts with significantly changed levels (false discovery rate (FDR) < 0.1; p < 0.1) in MPS cells vs. HDFa control varied in different MPS types, and was between 289 and 893 (Figure 1)
Expression of the following genes is significantly changed relative to HDFa control cells: CLU in MPS II, MFGE8 in MPS IIIA, HIP1 in MPS IIIB, COL5A1 in MPS IIIC, STS in MPS IIID, SCARA3 in MPS VI, MAN2A1 in MPS VII, and ATF5 in MPS IX. These results indicate that dysregulation of expression of the abovementioned genes may contribute to the appearance of the following disturbances in cellular and tissue-related processes: apoptosis, cell cycle regulation, and DNA repair in MPS II; phagocytosis, angiogenesis, atherosclerosis, tissue remodeling, and hemostasis regulation in MPS IIIA; endocytosis and cellular trafficking in MPS IIIB; functions of the connective tissue in MPS IIIC; production of estrogens, androgens, and cholesterol in MPS IIID; oxidative stress response in MPS VI; oligosaccharide (N-glycan) maturation in MPS VII; and cell differentiation and cellular adaptation to stress in MPS IX
Summary
Each of about 10,000 monogenic diseases, described to date [1], is caused by mutations in a single gene, symptoms of the vast majority of them are complex. In which almost 600,000 genomes of healthy persons were analyzed, led to the discovery of 13 cases of adults with no symptoms in which mutations of confirmed pathological effects occurred and that should result in manifestation of severe diseases in childhood [2]. While these results demonstrate a possibility of compensation of effects of particular mutations, giving hope for developing novel therapies, they indicate how far we are from understanding molecular processes leading to the development of particular genetic diseases. There are various therapeutic options for MPS, including enzyme replacement therapy, substrate reduction therapy, and hematopoietic stem cell transplantation, none of them provide a way to correct all, or even most, symptoms in humans [5,6]
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