Hurler syndrome: A patient with abnormally high levels of α-l-iduronidase protein

Abstract Mucopolysaccharidosis type I (MPS I: McKusick 25280) is a clinically heterogenous lysosomal storage disorder which is caused by a variable deficiency in α- l -iduronidase activity (α- l -iduronide iduronohydrolase, EC 3.2.1.76). Cultured fibroblasts from an MPS I patient (cell line 2827) with a severe clinical phenotype (Hurler syndrome) have been characterized using immunochemical and biochemical techniques. Using a specific immunoquantification assay, we have demonstrated that cell line 2827 had an α- l -iduronidase protein content (189 ng/mg of extracted cell protein) at least six times greater than the mean level found in normal control fibroblasts (30 ng/mg of extracted cell protein). This was the only MPS I cell line, from a group of 23 MPS I patients, that contained greater than 7% of the mean level of α- l -iduronidase protein detected in normal controls. Cell line 2827 had very low α- l -iduronidase activity toward the fluorogenic substrate 4-methylumbelliferyl-α- l -iduronide, and a radiolabeled disaccharide substrate derived from heparin. Maturation studies of α- l -iduronidase in cell line 2827 showed apparently normal levels of α- l -iduronidase synthesis with delayed processing to the mature form. Subcellular fractionation experiments demonstrated α- l -iduronidase protein in lysosomal-enriched fractions isolated from cell line 2827, suggesting a normal cell distribution and supporting the proposed delayed processing. It is proposed that the MPS I patient described has an α- l -iduronidase gene mutation which affects both the active site and post-translational processing of the enzyme. This mutation must be structurally conservative because it does not result in instability either during maturation or in the lysosome.