A hypothesis for I-cell disease: Defective hydrolases that do not enter lysosomes

Skin fibroblasts cultured from patients with I-cell disease ("I-cells") are markedly deficient in several lysosomal hydrolases, though these enzymes are found in surrounding medium. This situation is not brought about by increased lysosomal leakage, since I-cells were found as retentive of ingested enzymes (β-glucuronidase and α-L-iduronidase) as cells of other genotypes. On the other hand, hydrolases from I-cell medium were found only one-fifth to one-tenth as effective as their normal counterparts in experiments that involve uptake of the enzymes from the medium: correction of Hurler cells by α-L-iduronidase, correction of β-glucuronidase deficient cells by β-glucuronidase, and direct measurement of uptake of N-acetyl β-glucosaminidase by fibroblasts deficient in that enzyme. We suggest that the packaging of lysosomal enzymes requires their secretion followed by specific recognition and uptake. The I-cell mutation would interfere with this process by altering the recognition site on the hydrolases.