Mutations of glucocerebrosidase: discrimination of neurologic and non-neurologic phenotypes of Gaucher disease.

Multiple molecular forms of beta-glucocerebrosidase that permit discrimination between neurologic and non-neurologic phenotypes of Gaucher disease have been identified radioimmunologically in fibroblasts and human brain tissue. In normal human fibroblasts these forms have been shown by NaDodSO4/polyacrylamide gel electrophoresis to have apparent Mr of 63,000 (form A1), 61,000 (form A2), and 56,000 (form B). The Mr 63,000 form may be a precursor of the Mr 56,000 form. Non-neurologic Gaucher disease (type 1) fibroblasts and normal brain tissue are characteristic in that they contain only one major immunoreactive protein, the Mr 56,000 form. In contrast, fibroblast extracts and brain tissue from neurologic Gaucher disease phenotypes contain only the higher molecular weight forms A1 and A2. These data and the low residual activity of the enzyme in all the variants of Gaucher disease suggest that the mutations of beta-glucocerebrosidase are allelic and involve the active site.