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Journal of Lipid Research, Vol. 43, 1096-1104, July 2002
Copyright © 2002 by Lipid Research, Inc.

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

Befekadu Asfaw1,*, Jana Ledvinová*, Robert Dobrovolny*, Henk D. Bakker{dagger}, Robert J. Desnick§, Otto P. van Diggelen**, Jan G. N. de Jong{ddagger}, Tamotsu Kanzaki§§, Amparo Chabas***, Irene Maire{dagger}{dagger}{dagger}, Ernst Conzelmann§§§ and Detlev Schindler****

* Institute of Inherited Metabolic Disorders, First Faculty of Medicine, Charles University, 128 08 Prague, Czech Republic
{dagger} Children's Hospital, Academic Medical Centre, NL-1105 AZ Amsterdam, The Netherlands
§ Department of Human Genetics, Mount Sinai School of Medicine, New York, NY
** Department of Clinical Genetics, Erasmus University, NL-3000 DR Rotterdam, The Netherlands
{ddagger} Laboratory for Pediatrics and Neurology, University Medical Centre Nijmegen, NL-6525 GC Nijmegen, The Netherlands
§§ Department of Dermatology, Faculty of Medicine, Kagoshima University, Kagoshima, Japan
*** Instituto de Bioquimica Clinica, E-08290 Cerdanyola, Barcelona, Spain
{dagger}{dagger}{dagger} Laboratoire d'Enzymologie, F- 69322 Lyon, France
§§§ Department of Physiological Chemistry, Biozentrum, University of Wuerzburg, D-97074 Wuerzburg, Germany
**** Department of Human Genetics, Biozentrum, University of Wuerzburg, D-97074 Wuerzburg, Germany

1 To whom correspondence should be addressed. e-mail: basfaw{at}beba.cesnet.cz

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(ß1->4)GlcNAc(ß1->3)Gal(ß1-> 4)Glc (ß1->1')Cer, IV2-{alpha}-fucosyl-IV3-{alpha}-N-acetylgalactosaminylneolactotetraosylceramide), B-6-2 (Gal({alpha}1->3)[Fuc{alpha}1-> 2] Gal (ß1->4)GlcNAc(ß1->3)Gal(ß1->4)Glc(ß1->1')Cer, IV2- {alpha}-fucosyl-IV3-{alpha}-galactosylneolactotetraosylceramide), and globoside (GalNAc(ß1->3)Gal({alpha}1->4)Gal(ß1->4)Glc(ß1->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.

Abbreviations: A-6-2, blood group glycolipid A-6-2 (GalNAc ({alpha}1->3)[Fuc{alpha}1->2]Gal(ß1->4)GlcNAc(ß1->3)Gal(ß1->4)Glc(ß1->1')Cer, IV2-{alpha}-fucosyl-IV3-{alpha}-N-acetylgalactosaminylneolactotetraosylceramide); {alpha}-NAGA, {alpha}-N-acetylgalactosaminidase; B-6-2, blood group glycolipid B-6-2 (Gal({alpha}1->3)[Fuc{alpha}1->2]Gal(ß1->4)GlcNAc(ß1-> 3) Gal(ß1->4)Glc(ß1->1')Cer, IV2-{alpha}-fucosyl-IV3-{alpha}-galactosylneolactotetra- osylceramide); GbOse3Cer (Gal({alpha}1->4)Gal(ß1->4)Glc(ß1-> 1')Cer, globotriaosylceramide); globoside (GalNAc(ß1->3)Gal({alpha}1->4)Gal(ß1-> 4)Glc(ß1->1')Cer, globotetraosylceramide); mAb, mouse monoclonal antibody;

Supplementary key words {alpha}-N-acetylgalactosaminidase deficiency • {alpha}-galactosidase A deficiency • skin fibroblasts • in situ metabolism • lysosome targeting • blood group glycolipids • secretor status


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