Degradation of blood group A glycolipid A-6-2 by normal and mutant human skin fibroblasts.
The degradation of blood group glycolipid A-6-2 (GalNAc(alpha1-->3)[Fuc alpha1-->2]Gal(beta1-->4)GlcNAc(beta1-->3)Gal(beta1-->4)Glc(beta1-->1')C er, IV2-alpha-fucosyl-IV3-alpha-N-acetylgalactosaminylneolact otetraosylceramide), tritium-labeled in its ceramide moiety, was studied in situ, in skin fibroblast cultures from normal controls, from patients with defects of lysosomal alpha-N-acetylgalactosaminidase, and from patients with other lysosomal storage diseases. Uptake of the glycolipid with apolipoprotein E-coated liposomes was linear with time and with the amount of glycolipid added. In normal cells, the expected array of less polar products and some lipids resulting from re-using the liberated sphingosine, mainly sphingomyelin and phosphatidylcholine, were formed. In alpha-N-acetylgalactosaminidase-deficient cells, the glycolipid was virtually not degraded; product formation was less than 2% of the normal control rate, suggesting that blood group A-active glycolipids contribute as storage compounds to the pathogenesis of this disease. The expected accumulation of degradation intermediates was seen in fucosidosis, and in Sandhoff, Gaucher, and Farber disease cells, whereas normal turnover rates were found in Tay-Sachs disease cells, G(M2) activator-deficient (variant AB of G(M2) gangliosidosis) and in sulfatide activator- (sap-B-) deficient cells. In G(M1) gangliosidosis and in sap precursor-deficient cells, the lysosomal glycolipid catabolism was found to be strongly retarded; accumulation of individual products could not be seen. Skin fibroblasts from patients with alpha-N-acetylgalactosaminidase deficiency (Schindler disease) cannot degrade the major blood group A glycolipid.
Asfaw
B
B
Institute for Inherited Metabolic Diseases, First Faculty of Medicine and University Hospital, Charles University, Prague, Czech Republic.
Schindler
D
D
Ledvinová
J
J
Cerný
B
B
Smíd
F
F
Conzelmann
E
E
D000017:ABO Blood-Group System; D001057:Apolipoproteins E / Q000378:metabolism; D002236:Carbohydrate Conformation; D002240:Carbohydrate Sequence; D002478:Cells, Cultured; D005347:Fibroblasts / Q000378:metabolism*; D005645:Fucosidosis / Q000378:metabolism; D006028:Glycosphingolipids / Q000737:chemistry / Q000378:metabolism*; D006596:Hexosaminidases / Q000172:deficiency; D006801:Humans; D008081:Liposomes / Q000378:metabolism; D016464:Lysosomal Storage Diseases / Q000378:metabolism*; D008969:Molecular Sequence Data; D010713:Phosphatidylcholines / Q000378:metabolism; D012867:Skin / Q000378:metabolism; D013109:Sphingomyelins / Q000378:metabolism; D013110:Sphingosine / Q000378:metabolism; D014316:Tritium; D048809:alpha-N-Acetylgalactosaminidase
D000017:ABO Blood-Group System; D001057:Apolipoproteins E; D006028:Glycosphingolipids; D008081:Liposomes; D010713:Phosphatidylcholines; D013109:Sphingomyelins; C115696:blood group A glycolipid A-6-2; D014316:Tritium; D006596:Hexosaminidases; C482722:NAGA protein, human; D048809:alpha-N-Acetylgalactosaminidase; D013110:Sphingosine