Posttranslational processing of human lysosomal acid beta-glucosidase: a continuum of defects in Gaucher disease type 1 and type 2 fibroblasts.

The major processing steps in the maturation of the lysosomal hydrolase, acid beta-glucosidase, were examined in fibroblasts from normal individuals and from patients with types 1 and 2 Gaucher disease. In pulse-chase studies with normal fibroblasts, remodeling of N-linked oligosaccharides resulted in the temporal appearance of three molecular-weight forms of acid beta-glucosidase. An initial 64-kDa form, containing high mannose-type oligosaccharide side chains, was processed quantitatively, within 24 h, to a sialylated 69-kDa form. During the subsequent 96 h, some of the 69-kDa form is processed to 59 kDa. Glycosidase digestion studies revealed that the increase in the apparent molecular weight of the normal enzyme from 64 kDa to 69 kDa resulted primarily from the addition to sialic acid residues in the Golgi apparatus. The polypeptide backbone of both the 64-kDa and 69-kDa forms was 55.3 kDa. Processing of acid beta-glucosidase in fibroblasts from three of four type 1 (nonneuronopathic) Ashkenazi Jewish Gaucher disease patients was nearly normal. With fibroblasts from one Ashkenazi Jewish and three non-Jewish type 1 as well as from two type 2 (acute neuronopathic) Gaucher disease patients, only a 64-kDa form of acid beta-glucosidase was detected. Inefficient and incomplete processing to the 69-kDa form was found in one type 2 cell line (GM2627). These results indicate that no firm correlation exists between the type or degree of abnormal processing of acid beta-glucosidase in fibroblasts and the phenotype of Gaucher disease.