title: Genomic abnormalities of the murine model of Fabry disease after disease-related perturbation, a systems biology approach.
abstract: 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.
authors.affiliation: Section of Neurology, University of Manitoba, Winnipeg, MB, Canada R3T 2N2.
authors.forename: David F
authors.initials: DF
authors.lastname: Moore
authors.forename: Monique P
authors.initials: MP
authors.lastname: Gelderman
authors.forename: Paulo A
authors.initials: PA
authors.lastname: Ferreira
authors.forename: Steven R
authors.initials: SR
authors.lastname: Fuhrmann
authors.forename: Haiqing
authors.initials: H
authors.lastname: Yi
authors.forename: Abdel
authors.initials: A
authors.lastname: Elkahloun
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Lix
authors.forename: Roscoe O
authors.initials: RO
authors.lastname: Brady
authors.forename: Raphael
authors.initials: R
authors.lastname: Schiffmann
authors.forename: Ehud
authors.initials: E
authors.lastname: Goldin
mesh_terms: D000818:Animals; D003598:Cytoskeletal Proteins; D004195:Disease Models, Animal; D000795:Fabry Disease / Q000235:genetics* / Q000628:therapy; D016678:Genome; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011506:Proteins / Q000235:genetics; D049490:Systems Biology; D000519:alpha-Galactosidase / Q000627:therapeutic use
chemical_list: D003598:Cytoskeletal Proteins; D011506:Proteins; C415903:RPGRIP1 protein, human; D000519:alpha-Galactosidase