Fabry disease is a lysosomal storage disorder in which neutral glycosphingolipids, predominantly Gb3 (globotriaosylceramide), accumulate due to deficient α-Gal A (α-galactosidase A) activity. The GLAko (α-Gal A-knockout) mouse has been used as a model for Fabry disease, but it does not have any symptomatic abnormalities. In the present study, we generated a symptomatic mouse model (G3Stg/GLAko) by cross-breeding GLAko mice with transgenic mice expressing human Gb3 synthase. G3Stg/GLAko mice had high Gb3 levels in major organs, and their serum Gb3 level at 5–25 weeks of age was 6–10-fold higher than that in GLAko mice of the same age. G3Stg/GLAko mice showed progressive renal impairment, with albuminuria at 3 weeks of age, decreased urine osmolality at 5 weeks, polyuria at 10 weeks and increased blood urea nitrogen at 15 weeks. The urine volume and urinary albumin concentration were significantly reduced in the G3Stg/GLAko mice when human recombinant α-Gal A was administered intravenously. These data suggest that Gb3 accumulation is a primary pathogenic factor in the symptomatic phenotype of G3Stg/GLAko mice, and that this mouse line is suitable for studying the pathogenesis of Fabry disease and for preclinical studies of candidate therapies.
A symptomatic Fabry disease mouse model generated by inducing globotriaosylceramide synthesis
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Atsumi Taguchi, Hiroki Maruyama, Masaaki Nameta, Tadashi Yamamoto, Junichiro Matsuda, Ashok B. Kulkarni, Hidekatsu Yoshioka, Satoshi Ishii; A symptomatic Fabry disease mouse model generated by inducing globotriaosylceramide synthesis. Biochem J 15 December 2013; 456 (3): 373–383. doi: https://doi.org/10.1042/BJ20130825
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