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

Befekadu Asfaw, Jana Ledvinová, Robert Dobrovolný, Henk D. Bakker, Robert J. Desnick, Otto P. Van Diggelen, Jan G.N. De Jong, Tamotsu Kanzaki, Amparo Chabas, Irene Maire, Ernst Conzelmann, Detlev Schindler

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29 Scopus citations


Skin fibroblast cultures from patients with inherited lysosomal enzymopathies, α-N-acetylgalactosaminidase (α-NAGA) and α-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 (α1→3)[Fucα1→2]Gal(β1→4)GlcNAc(β1 →3)Gal(β1→4)Glc (β1→1′)Cer, IV2-α-fucosyl-IV3-α -N-acetylgalactosaminylneolactotetraosylceramide), B-6-2 (Gal(α1→3)[Fucα1→ 2] Gal (β1→4)GlcNAc(β1→3)Gal(β1→4)Glc(β1→1 ′)Cer, IV2-α-fucosyl-IV3-α -galactosylneolactotetraoslyceramide), and globoside (GalNAc(β1→3)Gal(α1→4)Gal(β1→4)Glc(β1 →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 α-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 α-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 α-D-Galactosyl moieties hints at a possible contribution of other enzymes.

Original languageEnglish
Pages (from-to)1096-1104
Number of pages9
JournalJournal of Lipid Research
Issue number7
StatePublished - 2002


  • Blood group glycolipids
  • In situ metabolism
  • Lysosome targeting
  • Secretor status
  • Skin fibroblasts
  • α-N-acetylgalactosaminidase deficiency
  • α-galactosidase A deficiency


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