iduronate and Intellectual-Disability

The properties of [35S]sulfate-labeled proteoglycans secreted by normal human skin fibroblasts were compared with those synthesized by fibroblasts from three patients with Coffin-Lowry syndrome. 60-80% of secreted radioactive macromolecules from normal fibroblasts were eluted from a Sepharose CL-4B column with a mean Kav-value of 0.56 (pool 2); 3-10% of the radioactivity appeared in the exclusion volume of the column (pool 1). In contrast, 17-60% of the proteoglycans from the patients were found in the void volume. The bulk of remaining material was eluted with a mean Kav-value of 0.47. Pool 2 glycan chains from two patients exhibited an increased hydrodynamic size. Pool 1 from normal cells contained predominantly a glucuronic acid-rich proteodermatan sulfate, iduronic acid amounting for approximately 20% of glucuronic acid. In the respective proteodermatan sulfate from the patients, the relative iduronic acid content was at least 33% of that of glucuronic acid. Pool 2 material of all cell lines was characterized predominantly as iduronic acid-rich proteodermatan sulfate. In the proteoglycans from two patients the content of chondroitin 4-sulfate-derived disaccharides was increased at the expense of 6-sulfated chondroitin disaccharides. Native proteoglycans from the patients were less efficiently endocytosed by fibroblasts than their normal counterparts. Coffin-Lowry fibroblasts had a normal capability to synthesize glycosaminoglycan chains on an artificial acceptor, p-nitrophenyl-beta-D-xyloside. They were also normal in 3'-phosphoadenylylsulfate: chondroitin 4- and 6-sulfotransferase activities.

Topics: Abnormalities, Multiple; Adult; Bone and Bones; Cells, Cultured; Child, Preschool; Chondroitin; Dermatan Sulfate; Fibroblasts; Glucuronates; Glucuronic Acid; Humans; Iduronic Acid; Intellectual Disability; Male; Proteoglycans; Sex Factors; Skin; Skin Diseases; Syndrome

Skin fibroblasts cultured from patients affected with the Hunter syndrome are deficient in the activity of a protein, named the "Hunter corrective factor," that is required for degradation of dermatan and heparan sulfates. We now show that this factor, purified from human urine, removes about 2% of the sulfate residues from [(35)S]mucopolysaccharide accumulated within Hunter fibroblasts; these groups are derived from "oversulfated" regions of the polymer. Acetone-powder extracts of fibroblasts derived from patients with the Hunter syndrome are deficient in this sulfatase, in contrast to similar extracts from fibroblasts of individuals of other genotype. Hunter corrective factor coupled to alpha-L-iduronidase (or alternatively, mixed extracts from Hurler and Hunter fibroblasts) release iduronic acid from 4-O-alpha-L-sulfoiduronosyl-D-sulfoanhydromannose. We conclude that the Hunter corrective factor is a sulfatase for sulfated iduronic acid residues.

Topics: Carbohydrate Metabolism, Inborn Errors; Cells, Cultured; Fibroblasts; Galactose; Glucosamine; Glucuronidase; Glycosaminoglycans; Glycosides; Humans; Iduronic Acid; Intellectual Disability; Mannose; Mucopolysaccharidosis II; Retinitis Pigmentosa; Skin; Sulfatases; Sulfur Isotopes; Sulfuric Acids; Tritium; Uronic Acids