Fabry disease is an X-linked inherited metabolic disorder that is caused by a deficiency of α-galactosidase A (α-Gal A). Progressive deposition of neutral glycosphingolipids that have terminal α-linked galactosyl moieties in vascular endothelial cells causes renal failure along with premature myocardial infarctions and strokes in patients with this condition. No specific treatment is available for patients with this disorder at this time. An animal model of this condition would be valuable for exploring therapeutic strategies for patients with Fabry disease. We report here the generation of α-Gal A deficient mice by gene targeting and an analysis of the resulting phenotype. The knockout mice display a complete lack of α-Gal A activity. The mice, however, appeared clinically normal at 10 weeks of age. Ultrastructural analysis revealed concentric lamellar inclusions in the kidneys, and confocal microscopy using a fluorescent-labeled lectin specific for α-D-galactosyl residues showed accumulation of substrate in the kidneys as well as in cultured fibroblasts. Lipid analysis revealed a marked accumulation of ceramidetrihexoside in the liver and the kidneys. These findings indicate the similarity of the pathophysiological process in the mutant mice and in patients with Fabry disease. The deficiency of α-Gal A activity and the accumulation of material containing terminal α-galactosyl residues in cultured embryonic fibroblasts derived from α-Gal A (-/0) mice were corrected by transducing these cells with bicistronic multidrug resistance retroviruses containing human α-Gal A cDNA.
|Proceedings of the National Academy of Sciences of the United States of America
|Published - 1997 3月 18
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