Study of the Hurler syndrome using cell culture: definition of the biochemical phenotype and the effects of ascorbic acid on the mutant cell.

Fibroblasts from patients with Hurler syndrome retain a distinctive biochemical phenotype when grown in culture which is characterized by increased synthesis of both nonsulfated and sulfated glycosaminoglycans. Ascorbic acid reinforces the phenotypic expression of the biochemical abnormality, producing not only increased synthesis of sulfated glycosaminoglycans, but selective retention of sulfated glycosaminoglycans within the cell. Although the synthesis of nonsulfated glycosaminoglycans is also increased, these compounds, particularly hyaluronic acid are not retained by the cell but are secreted into the medium. Analyses of urine from patients with Hurler syndrome show increased absolute concentrations of nonsulfated glycosaminoglycans in addition to the expected increase in sulfated glycosaminoglycans. This indicates that the biochemical phenotype as defined in cell culture is not an artifact of the experimental model but reflects the biochemical defect in the patient. Redefinition of the biochemical defect to include nonsulfated as well as sulfated glycosaminoglycans contradicts explanations of this disease which are based on a single structural gene mutation.