ALPHA-GALACTOSIDASE A DEFICIENT MICE - A MODEL OF FABRY DISEASE

Fabry disease is an X-linked inherited metabolic disorder that is caus ed by a deficiency of alpha-galactosidase A (alpha-Gal A). Progressive deposition of neutral glycosphingolipids that have terminal alpha-lin ked galactosyl moieties in vascular endothelial cells causes renal fai lure along with premature myocardial infarctions and strokes in patien ts with this condition, No specific treatment is available for patient s with this disorder at this time, An animal model of this condition w ould be valuable for exploring therapeutic strategies for patients wit h Fabry disease, We report here the generation of alpha-Gal A deficien t mice by gene targeting and an analysis of the resulting phenotype. T ile knockout mice display a complete lack of alpha-Gal A activity. The mice, however, appeared clinically normal at 10 weeks of age. Ultrast ructural analysis revealed concentric lamellar inclusions in the kidne ys, and confocal microscopy using a fluorescent-labeled lectin specifi c for alpha-D-galactosyl residues showed accumulation of substrate in the kidneys as web as in cultured fibroblasts, Lipid analysis revealed a marked accumulation of ceramidetrihexoside in the liver and the kid neys. These findings indicate the similarity of the pathophysiological process in the mutant mice and in patients with Fabry disease, The de ficiency of alpha-Gal A activity and the accumulation of material cont aining terminal alpha-galactosyl residues in cultured embryonic fibrob lasts derived from alpha-Gal A(-/0) mice were corrected by transducing these cells with bicistronic multidrug resistance retroviruses contai ning human alpha-Gal A cDNA.