The
lysosomal storage disease MPS VII (
mucopolysaccharidosis type VII) is caused by a deficiency in
beta-glucuronidase activity, and results in the accumulation of partially degraded
glycosaminoglycans in many cell types. Although MPS VII is a simple monogenetic disorder, the clinical presentation is complex and incompletely understood. ERT (
enzyme replacement therapy) is relatively effective at improving the
clinical course of the disease; however, some pathologies persist. In order to clarify the molecular events contributing to the disease phenotype and how ERT might impact upon them, we analysed liver tissue from untreated and treated MPS VII mice at both 2 and 5 months of age using biochemical assays and microarray analysis. Overall, as the disease progresses, more genes have altered expression and, at either age, numerous transcriptional changes in multiple pathways appear to be refractory to
therapy. With respect to the primary site of disease, both transcriptional and post-transcriptional mechanisms are involved in the regulation of lysosomal
enzymes and other lysosome-associated
proteins. Many of the changes observed in both lysosome-associated mRNAs and
proteins are normalized by
enzyme replacement. In addition, gene expression changes in seemingly unrelated pathways may account for the complex metabolic phenotype of the MPS VII mouse. In particular,
beta-glucuronidase deficiency appears to induce physiological
malnutrition in MPS VII mice.
Malnutrition may account for the pronounced adipose storage deficiency observed in this animal. Studying the molecular response to lysosomal storage, especially those changes recalcitrant to
therapy, has revealed additional targets that may improve the efficacy of existing
therapies.