title: Secondary storage of dermatan sulfate in Sanfilippo disease.
abstract: Mucopolysaccharidoses are a group of genetically inherited disorders that result from the defective activity of lysosomal enzymes involved in glycosaminoglycan catabolism, causing their intralysosomal accumulation. Sanfilippo disease describes a subset of mucopolysaccharidoses resulting from defects in heparan sulfate catabolism. Sanfilippo disorders cause severe neuropathology in affected children. The reason for such extensive central nervous system dysfunction is unresolved, but it may be associated with the secondary accumulation of metabolites such as gangliosides. In this article, we describe the accumulation of dermatan sulfate as a novel secondary metabolite in Sanfilippo. Based on chondroitinase ABC digestion, chondroitin/dermatan sulfate levels in fibroblasts from Sanfilippo patients were elevated 2-5-fold above wild-type dermal fibroblasts. Lysosomal turnover of chondroitin/dermatan sulfate in these cell lines was significantly impaired but could be normalized by reducing heparan sulfate storage using enzyme replacement therapy. Examination of chondroitin/dermatan sulfate catabolic enzymes showed that heparan sulfate and heparin can inhibit iduronate 2-sulfatase. Analysis of the chondroitin/dermatan sulfate fraction by chondroitinase ACII digestion showed dermatan sulfate storage, consistent with inhibition of iduronate 2-sulfatase. The discovery of a novel storage metabolite in Sanfilippo patients may have important implications for diagnosis and understanding disease pathology.
authors.affiliation: Department of Cellular and Molecular Medicine, Glycobiology Research and Training Center, University of California, San Diego, La Jolla, California 92093-0687, USA.
authors.forename: William C
authors.initials: WC
authors.lastname: Lamanna
authors.forename: Roger
authors.initials: R
authors.lastname: Lawrence
authors.forename: Stéphane
authors.initials: S
authors.lastname: Sarrazin
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Esko
mesh_terms: D002478:Cells, Cultured; D002809:Chondroitin Sulfates / Q000378:metabolism / Q000494:pharmacology; D003871:Dermatan Sulfate / Q000378:metabolism* / Q000494:pharmacology; D056947:Enzyme Replacement Therapy / Q000379:methods; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D005966:Glucuronidase / Q000037:antagonists & inhibitors / Q000378:metabolism; D006497:Heparan Sulfate / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D006867:Hydrolases / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology; D007066:Iduronate Sulfatase / Q000037:antagonists & inhibitors / Q000378:metabolism; D066298:In Vitro Techniques; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism*; D009084:Mucopolysaccharidosis III / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology
chemical_list: D002809:Chondroitin Sulfates; D003871:Dermatan Sulfate; D005966:Glucuronidase; D006497:Heparan Sulfate; D006867:Hydrolases; D007066:Iduronate Sulfatase; C022708:N-sulfoglucosamine sulfohydrolase