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

doi:10.1073/pnas.0701991104

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

*Section of Neurology,
**Department of Community Health Sciences, University of Manitoba, Winnipeg, MB, Canada R3T 2N2;
^†Laboratory of Cellular Hematology, Center for Biologics Evaluation and Research, Food and Drug Administration, Rockville, MD 20857;
^¶IOMAI Corporation, Gaithersburg, MD 20878;
^‡Departments of Ophthalmology and
^§Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710;
^‖National Institute of Neurological Disorders and Strokes, Micro-Array Core Facility, Bethesda, MD 20892; and
^††Developmental and Metabolic Neurology Branch, National Institute of Neurological Disorders and Strokes/National Institutes of Health, Bethesda, MD 20892

Contributed by Roscoe O. Brady, March 20, 2007 (received for review February 26, 2007)

Abstract

Fabry disease is a disorder of α-d-galactosyl-containing glycolipids resulting from a deficiency of α-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 α-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 α-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 α-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.

Footnotes

^‡‡To whom correspondence may be addressed. E-mail: rb57v{at}nih.gov or rs4e{at}nih.gov
Author contributions: D.F.M., M.P.G., R.O.B., and E.G. designed research; D.F.M., M.P.G., S.R.F., H.Y., P.A.F., A.E., and E.G. performed research; S.R.F., H.Y., P.A.F., and A.E. contributed new reagents/analytic tools; D.F.M., H.Y., P.A.F., L.M.L., R.S., and E.G. analyzed data; and D.F.M., M.P.G., P.A.F., L.M.L., R.O.B., R.S., and E.G. wrote the paper.
The authors declare no conflict of interest.
This article contains supporting information online at www.pnas.org/cgi/content/full/0701991104/DC1.
Abbreviations:

AGFI,

adjusted goodness-of-fit index;

BIC,

Bayesian information criterion;

CFA,

confirmatory factor analysis;

CI,

confidence intervals;

ERT,

enzyme replacement therapy;

FDR,

false discovery rate;

FWE,

family-wise error;

GFI,

goodness-of-fit index;

KO,

knockout;

MCC,

multiple comparison correction;

ML,

maximum likelihood;

MLE,

maximum likelihood estimator;

NFI,

normed fit index;

RMSEA,

root mean square error of approximation;

ROS,

reactive oxygen species;

SEM,

structural equation modeling.
Freely available online through the PNAS open access option.