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

doi:10.1194/jlr.M100423-JLR200

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

Befekadu Asfaw¹^,*, Jana Ledvinová^*, Robert Dobrovol $n$ y^*, Henk D. Bakker, Robert J. Desnick, Otto P. van Diggelen^**, Jan G. N. de Jong, Tamotsu Kanzaki, Amparo Chabas^***, Irene Maire, Ernst Conzelmann and Detlev Schindler^****

^* Institute of Inherited Metabolic Disorders, First Faculty of Medicine, Charles University, 128 08 Prague, Czech Republic
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
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
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 lysosomalenzymopathies, ${alpha}$ -N-acetylgalactosaminidase ( ${alpha}$ -NAGA) and ${alpha}$ -galactosidaseA deficiencies (Schindler and Fabry disease, respectively),and from normal controls were used to study in situ degradationof blood group A and B glycosphingolipids. GlycosphingolipidsA-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), andgloboside (GalNAc(ß1 $->$ 3)Gal( ${alpha}$ 1 $->$ 4)Gal(ß1 $->$ 4)Glc(ß1 $->$ 1')Cer, globotetraosylceramide) were tritium labeled in their ceramidemoiety and used as natural substrates. The degradation rateof glycolipid A-6-2 was very low in fibroblasts of all the ${alpha}$ -NAGA-deficientpatients (less than 7% of controls), despite very heterogeneousclinical pictures, ruling out different residual enzyme activitiesas an explanation for the clinical heterogeneity. Strongly elevatedurinary excretion of blood group A glycolipids was detectedin one patient with blood group A, secretor status (five timeshigher than upper limit of controls), in support of the notionthat blood group A-active glycolipids may contribute as storagecompounds in blood group A patients. When glycolipid B-6-2 wasfed to ${alpha}$ -galactosidase A-deficient cells, the degradation ratewas surprisingly high (50% of controls), while that of globotriaosylceramidewas reduced to less than 15% of control average, presumablyreflecting differences in the lysosomal enzymology of polarglycolipids versus less-polar ones.

Relatively high-degree degradation of substrates with ${alpha}$ -D-Galactosylmoieties 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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