title: 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.affiliation: Institute of Inherited Metabolic Disorders, First Faculty of Medicine, Charles University, 128 08 Prague, Czech Republic. basfaw@beba.cesnet.cz
authors.forename: Befekadu
authors.initials: B
authors.lastname: Asfaw
authors.forename: Jana
authors.initials: J
authors.lastname: Ledvinová
authors.forename: Robert
authors.initials: R
authors.lastname: Dobrovolńy
authors.forename: Henk D
authors.initials: HD
authors.lastname: Bakker
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Desnick
authors.forename: Otto P
authors.initials: OP
authors.lastname: van Diggelen
authors.forename: Jan G N
authors.initials: JG
authors.lastname: de Jong
authors.forename: Tamotsu
authors.initials: T
authors.lastname: Kanzaki
authors.forename: Amparo
authors.initials: A
authors.lastname: Chabas
authors.forename: Irene
authors.initials: I
authors.lastname: Maire
authors.forename: Ernst
authors.initials: E
authors.lastname: Conzelmann
authors.forename: Detlev
authors.initials: D
authors.lastname: Schindler
mesh_terms: D000017:ABO Blood-Group System / Q000737:chemistry* / Q000378:metabolism*; D000293:Adolescent; D000328:Adult; D002460:Cell Line; D002648:Child; D002675:Child, Preschool; D000795:Fabry Disease / Q000097:blood / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D005347:Fibroblasts; D006028:Glycosphingolipids / Q000097:blood / Q000378:metabolism* / Q000652:urine; D006596:Hexosaminidases / Q000172:deficiency; D006801:Humans; D012867:Skin; D048809:alpha-N-Acetylgalactosaminidase
chemical_list: D000017:ABO Blood-Group System; D006028:Glycosphingolipids; D006596:Hexosaminidases; C482722:NAGA protein, human; D048809:alpha-N-Acetylgalactosaminidase