Defects in degradation of blood group A and B glycosphingolipids in Schindler and Fabry diseases

Abstract Skin fibroblast cultures from patients with inherited lysosomal enzymopathies, -N-acetylgalactosaminidase (-NAGA) and -galactosidase A deficiencies (Schindler and Fabry disease, respectively), and from normal controls were used to study in situ degradation of blood group A and B glycosphingolipids. Glycosphingolipids A-6-2 (GalNAc (1→3)[Fuc1→2]Gal(1→4)GlcNAc(1→3)Gal(1→ 4)Glc (1→1)Cer, IV2--fucosyl-IV3--N-acetylgalactosaminylneolactotetraosylceramide), B-6-2 (Gal(1→3)[Fuc1→ 2] Gal (1→4)GlcNAc(1→3)Gal(1→4)Glc(1→1)Cer, IV2- -fucosyl-IV3--galactosylneolactotetraosylceramide), and globoside (GalNAc(1→3)Gal(1→4)Gal(1→4)Glc(1→1) Cer, globotetraosylceramide) were tritium labeled in their ceramide moiety and used as natural substrates. The degradation rate of glycolipid A-6-2 was very low in fibroblasts of all the -NAGA-deficient patients (less than 7% of controls), despite very heterogeneous clinical pictures, ruling out different residual enzyme activities as an explanation for the clinical heterogeneity. Strongly elevated urinary excretion of blood group A glycolipids was detected in one patient with blood group A, secretor status (five times higher than upper limit of controls), in support of the notion that blood group A-active glycolipids may contribute as storage compounds in blood group A patients. When glycolipid B-6-2 was fed to -galactosidase A-deficient cells, the degradation rate was surprisingly high (50% of controls), while that of globotriaosylceramide was reduced to less than 15% of control average, presumably reflecting differences in the lysosomal enzymology of polar glycolipids versus less-polar ones. Relatively high-degree degradation of substrates with -d-Galactosyl moieties hints at a possible contribution of other enzymes.