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

Journal of Lipid Research

Jana Ledvinová¹  Robert J. Desnick²  Jan G.N. de Jong³  Amparo Chabas⁴  Otto P. van Diggelen⁵  Detlev Schindler⁶  Robert Dobrovolńy⁷  Henk D. Bakker⁷  Irene Maire⁸  Ernst Conzelmann⁹  Tamotsu Kanzaki^1,10  Befekadu Asfaw^1,11 

[1] 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 Clinical Genetics, Erasmus University, NL-3000 DR Rotterdam, The Netherlands;Department of Dermatology, Faculty of Medicine, Kagoshima University, Kagoshima, Japan;Department of Human Genetics, Mount Sinai School of Medicine, New York, NY;Department of Physiological Chemistry, Biozentrum, University of Wuerzburg, D-97074 Wuerzburg, Germany;Institute of Inherited Metabolic Disorders, First Faculty of Medicine, Charles University, 128 08 Prague, Czech Republic;Instituto de Bioquimica Clinica, E-08290 Cerdanyola, Barcelona, Spain;Laboratoire d'Enzymologie, F- 69322 Lyon, France;Laboratory for Pediatrics and Neurology, University Medical Centre Nijmegen, NL-6525 GC Nijmegen, The Netherlands;To whom correspondence should be addressed;

关键词: α-N-acetylgalactosaminidase deficiency;    α-galactosidase A deficiency;    skin fibroblasts;    in situ metabolism;    lysosome targeting;    blood group glycolipids;   

DOI  :  

来源: DOAJ

【 摘 要 】

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-galactosylneolactotetraosylceramide), 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.

【 授权许可】

Unknown