Numerous transcriptional alterations in liver persist after short-term enzyme-replacement therapy in a murine model of mucopolysaccharidosis type VII

Josh C. Woloszynek, Marie Roberts, Trey Coleman, Carole Vogler, William Sly, Clay F. Semenkovich, Mark S. Sands

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

Abstract

The lysosomal storage disease MPS VII (mucopolysaccharidosis type VII) is caused by a deficiency in β-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, β-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.

Original languageEnglish
Pages (from-to)461-469
Number of pages9
JournalBiochemical Journal
Volume379
Issue number2
DOIs
StatePublished - Apr 15 2004

Keywords

  • Enzyme replacement
  • Lysosomal storage
  • Mucopolysaccharidosis
  • Sly syndrome
  • β-glucuronidase

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