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, alpha-N-acetylgalactosaminidase (alpha-NAGA) and alpha-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 (alpha 1-->3)[Fuc alpha 1-->2]Gal(beta1-->4)GlcNAc(beta 1-->3)Gal(beta 1--> 4)Glc (beta 1-->1')Cer, IV(2)-alpha-fucosyl-IV(3)-alpha-N-acetylgalactosaminylneolactotetraosylceramide), B-6-2 (Gal(alpha 1-->3)[Fuc alpha 1--> 2] Gal (beta 1-->4)GlcNAc(beta 1-->3)Gal(beta 1-->4)Glc(beta 1-->1')Cer, IV(2)- alpha-fucosyl-IV(3)-alpha-galactosylneolactotetraosylceramide), and globoside (GalNAc(beta 1-->3)Gal(alpha 1-->4)Gal(beta 1-->4)Glc(beta 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 alpha-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 alpha-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 alpha-D-Galactosyl moieties hints at a possible contribution of other enzymes.

• Authors: Befekadu Asfaw, Jana Ledvinová, Robert Dobrovolńy, 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
• Journal: Journal of lipid research (J Lipid Res) Vol. 43 Issue 7 Pg. 1096-104 (Jul 2002) ISSN: 0022-2275 [Print] United States
• PMID: 12091494 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ABO Blood-Group System
• Glycosphingolipids
• Hexosaminidases
• NAGA protein, human
• alpha-N-Acetylgalactosaminidase

Topics

• ABO Blood-Group System (chemistry, metabolism)
• Adolescent
• Adult
• Cell Line
• Child
• Child, Preschool
• Fabry Disease (blood, enzymology, metabolism, pathology)
• Fibroblasts
• Glycosphingolipids (blood, metabolism, urine)
• Hexosaminidases (deficiency)
• Humans
• Skin
• alpha-N-Acetylgalactosaminidase