Genetic Base of Behavioral Disorders in Mucopolysaccharidoses: Transcriptomic Studies

Abstract

Mucopolysaccharidoses (MPS) are a group of inherited metabolic diseases caused by mutations leading to defective degradation of glycosaminoglycans (GAGs) and their accumulation in cells. Among 11 known types and subtypes of MPS, neuronopathy occurs in seven (MPS I, II, IIIA, IIIB, IIIC, IIID, VII). Brain dysfunctions, occurring in these seven types/subtypes include various behavioral disorders. Intriguingly, behavioral symptoms are significantly different between patients suffering from various MPS types. Molecular base of such differences remains unknown. Here, we asked if expression of genes considered as connected to behavior (based on Gene Ontology, GO terms) is changed in MPS. Using cell lines of all MPS types, we have performed transcriptomic (RNA-seq) studies and assessed expression of genes involved in behavior. We found significant differences between MPS types in this regard, with the most severe changes in MPS IIIA (the type considered as the behaviorally most severely affected), while the lowest changes in MPS IVA and MPS VI (types in which little or no behavioral disorders are known). Intriguingly, relatively severe changes were found also in MPS IVB (in which, despite no behavioral disorder noted, the same gene is mutated as in GM1 gangliosidosis, a severe neurodegenerative disease) and MPS IX (in which only a few patients were described to date, thus, behavioral problems are not well recognized). More detailed analyses of expression of certain genes allowed us to propose an association of specific changes in the levels of transcripts in specific MPS types to certain behavioral disorders observed in patients. Therefore, this work provides a principle for further studies on the molecular mechanism of behavioral changes occurring in MPS patients.

Transcriptomic analyses suggest that mucopolysaccharidosis patients may be less susceptible to COVID‐19

“…The question what is the specific cause of changes in expression of tested genes in MPS cells remains unanswered. As indicated in recently published reports [12–14], expression of hundreds of genes is changed in MPS cells relative to controls. Specific mechanisms of these regulations remain to be elucidated; however, it was proposed that they reflect secondary and tertiary changes in cellular processes, after primary GAG storage [32].…”

“…Thus, one might suspect that such patients might be a high risk group for COVID‐19; however, no reports were published to date on COVID‐19 in MPS. On the other hand, recent studies indicated that in cells of MPS patients, there are hundreds of genes which expression is significantly changed relative to healthy persons [12–14]. This might potentially modify susceptibility of these patients to infection by SARS‐CoV‐2.…”

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

“…4), suggesting that there are groups of processes similarly changed in all these types, despite evident specificity of each type. Although experiments presented in this report were performed on fibroblasts, specific changes in expressions of regulatory proteins might, to some extent, be extrapolated to other cell types, including neurons as discussed previously (Pierzynowska et al 2020), suggesting that they could contribute to neurodegenerative processes occurring in MPS.…”

“…Recent studies clearly indicated that secondary and tertiary changes (after the primary GAG storage) in cellular processes contribute significantly to the development of disorders and symptoms appearing in the course of MPS (Gaffke et al 2019;Fecarotta et al 2020). Significance of this aspect of MPS pathomechanism has been highlighted recently by discoveries of multiple changes in expression of genes coding for proteins involved in various cellular mechanisms in MPS (Brokowska et al 2020;Gaffke et al 2020;Pierzynowska et al 2020;Rintz et al 2020). Therefore, in this work, we have analyzed transcriptomic data, focusing on expression of genes coding for regulatory proteins responsible for the control of cellular processes.…”

“…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. In such a way, it was possible to preliminarily identify the genes whose changed expression in MPS cells might be responsible for or contribute to disorders in various cellular processes, including apoptosis (Brokowska et al 2020) and cell activation (Rintz et al 2020), or even to disturbance in behavioral disorders (Pierzynowska et al 2020). This has encouraged us to ask what genes coding for proteins involved in regulation of cellular processes reveal changed expression in MPS cells relative to controls.…”