Genomic abnormalities of the murine model of Fabry disease after disease-related perturbation, a systems biology approach.

Journal Article (Journal Article)

Fabry disease is a disorder of alpha-D-galactosyl-containing glycolipids resulting from a deficiency of alpha-galactosidase A. Patients have a poorly understood vascular dysregulation. We hypothesized that disease-related perturbation by using enzyme replacement therapy in the murine model of Fabry disease would provide insight into abnormal biological processes in Fabry disease. Gene expression analyses of the heart, aorta, and liver of male alpha-galactosidase A knockout mice 28 weeks of age were compared with that of WT mice. Microarray analyses were performed before and after six weekly injections of alpha-galactosidase A. Alteration of Rpgrip1 ranked highest statistically in all three organs when knockout mice were compared with WT, and its splice variants responded in a unique way to alpha-galactosidase A. Enzyme replacement therapy tended to not only normalize gene expression, e.g., reduce the overexpression of securin, but also specifically modified gene expression in each tissue examined. Following multiple comparison analysis, gene expression correlation graphs were constructed, and a priori hypotheses were examined by using structural equation modeling. This systems biology approach demonstrated multiple and complex parallel cellular abnormalities in Fabry disease. These abnormalities form the basis for informed, in a Bayesian sense, sequential, hypothesis-driven research that can be subsequently tested experimentally.

Full Text

Duke Authors

Cited Authors

  • Moore, DF; Gelderman, MP; Ferreira, PA; Fuhrmann, SR; Yi, H; Elkahloun, A; Lix, LM; Brady, RO; Schiffmann, R; Goldin, E

Published Date

  • May 8, 2007

Published In

Volume / Issue

  • 104 / 19

Start / End Page

  • 8065 - 8070

PubMed ID

  • 17470787

Pubmed Central ID

  • PMC1859990

International Standard Serial Number (ISSN)

  • 0027-8424

Digital Object Identifier (DOI)

  • 10.1073/pnas.0701991104


  • eng

Conference Location

  • United States