α‐Galactosidase A‐deficient rats accumulate glycosphingolipids and develop cardiorenal phenotypes of Fabry disease

Abstract

Fabry disease is an X-linked lysosomal storage disease caused by α-galactosidase A (α-Gal A) deficiency. Kidney and heart failure are frequent complications in adulthood and greatly contribute to patient morbidity and mortality. Because α-Gal A-deficient mouse models do not recapitulate cardiorenal findings observed in patients, a nonmouse model may be beneficial to our understanding of disease pathogenesis. In this study, we evaluated disease processes in a recently generated Fabry rat model. We found that male Fabry rats weighed significantly less than wild-type (WT) males, whereas female Fabry rats weighed significantly more than WT females. Whereas no difference in female survival was detected, we observed that male Fabry rats had a decreased lifespan. Skin histology revealed that inflammation and lipoatrophy may be chief disease mediators in patients. With respect to the kidney and heart, we found that both organs accumulate α-Gal A substrates, including the established biomarkers, globotriaosylceramide and globotriaosylsphingosine. Longitudinal serum and urine chemistry panels demonstrated pronounced renal tubule dysfunction, which was confirmed histologically. Mitral valve thickening was observed in Fabry rats using echocardiography. We conclude that Fabry rats recapitulate important kidney and heart phenotypes experienced by patients and can be further used to study disease mechanisms and test therapies.-Miller, J. J., Aoki, K., Mascari, C. A., Beltrame, A. K., Sokumbi, O., North, P. E., Tiemeyer, M., Kriegel, A. J., Dahms, N. M., α-Galactosidase A-deficient rats accumulate glycosphingolipids and develop cardiorenal phenotypes of Fabry disease.

Fabry Disease: Molecular Basis, Pathophysiology, Diagnostics and Potential Therapeutic Directions

“…However, clinical symptoms develop only late in life. The same discrepancy is noted in α-GalA-deficient FD mice and rats [29,30]. Lipid-laden macrophages have been observed in the liver of classic FD males.…”

Auditory brainstem responses in aging dark agouti rats

“…With the mean survival of male DA rats at 2 years (Fig. 2), it is possible that these data are consistent with aging being associated with the observed hearing loss [35]. However, we cannot rule out the possibility that other factors contribute to the observed hearing loss in male DA rats.…”

Rats deficient in α-galactosidase A develop ocular manifestations of Fabry disease

“…Similar to our previous studies on Fabry rat pain, cardiac, and renal phenotypes 15,16 , we next aimed to characterize the ocular phenotypes at the molecular and cellular levels. Given that patients with Fabry disease are deficient in α-Gal A, they accumulate glycosphingolipids terminated with galactose (Gal) residues in an α-linkage.…”

“…α-Gal A knockout (KO) mouse models have been important in evaluating therapies to diminish glycosphingolipid storage 13,14 , but the utility of the Fabry mouse in studying eye pathology is limited by the fact that ocular phenotypes are not robustly documented in Fabry mice. We previously generated an α-Gal A KO (Fabry) rat model, which demonstrates pain, cardiac, and renal phenotypes commonly observed in patients 15,16 . In this study, we evaluated the corneal, lenticular, and retinal phenotypes of Fabry rats.…”