Expression of genes involved in apoptosis is dysregulated in mucopolysaccharidoses as revealed by pilot transcriptomic analyses

Mucopolysaccharidoses (MPS), a group of lysosomal storage diseases (LSD), are inherited disorders caused by mutations in genes coding for enzymes involved in the degradation of glycosaminoglycans (GAGs). Therefore, accumulated GAGs in lysosomes lead to severe symptoms in patients and significantly shortened life span. Although GAG accumulation in cells is the primary cellular defect in MPS, recent reports indicated that severe changes in cellular processes occur there as secondary or tertiary effects, which may contribute significantly to the disease pathomechanism. Apoptosis is one of such process, while mechanisms leading to dysregulation of this process in MPS remain largely unknown. To learn about these mechanisms, we have performed transcriptomic studies using cultures of fibroblasts derived from patients suffering from all types and subtypes of MPS, and assessed genes related to apoptosis. We found that there are significant changes in expression levels of many such genes relative to control fibroblasts (Human Dermal Fibroblasts-adult cell line), and the number of down- or up-regulated transcripts was between 19 and 73 in different MPS types. We have identified apoptosis-related genes, which were considerably dysregulated in many MPS types, as well as those in which expression was significantly changed in specific MPS types. BNIP3, C1D, CLU, GPER1, KREMEN1, and PRKCD genes displayed the most changed expression profiles in most MPS types relative to control cells. Caspase 3/7 activity was increased in MPS IVA and IX. These results indicate that changes in apoptosis, observed in MPS, may arise, at least partially, from dysregulation of genes coding for proteins involved in this process.