GAUCHER DISEASE TYPE-1, TYPE-2, AND TYPE-3 - DIFFERENTIAL MUTATIONS OF THE ACID BETA-GLUCOSIDASE ACTIVE-SITE IDENTIFIED WITH CONDURITOL-B EPOXIDE DERIVATIVES AND SPHINGOSINE

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  • 1 January 1985
    • journal article
    • research article
    • Vol. 37  (3) , 499-510
Abstract
To elucidate the genetic heterogeneity in Gaucher disease, the residual 7b-glucosidase in cultured fibroblasts from affected patients with each of the major phenotypes was investigated in vitro and/or in viable cells by inhibitor studies using the covalent catalytic site inhibitors, conduritol B epoxide or its bromo derivative, and the reversible cationic inhibitor, sphingosine. These studies delineated 3 distinct groups (designated A, B and C) of residual activities with characteristic responses to these inhibitors. Group A residual enzymes had normal I50 values (i.e., the concentration of inhibitor that results in 50% inhibition) for the inhibitors and normal or nearly normal t1/2 [half-time] values for conduritol B epoxide. All neuronopathic (types 2 and 3) and most non-Jewish nonneuronopathic (type 1) patients had group A residual activities and could not be distinguished by these inhibitor studies. Group B residual enzymes had about 4- to 5-fold increased I50 values for the inhibitors and similarly increased t1/2 values for conduritol B epoxide. All Ashkenazi Jewish type 1 and only 2 non-Jewish type 1 patients had group B residual activities. The differences in I50 values between groups A and B also were confirmed by determining the uninhibited enzyme activity after culturing the cells in the presence of bromo-conduritol B epoxide. Group C residual activity had intermediate I50 values for the inhibitors and represented a single Afrikaner type 1 patient: this patient was a genetic compound for the group A (type 2) and group B (type 1) mutations. These inhibition studies indicated that: Gaucher disease type 1 is biochemically heterogeneous, neuronopathic and non-Jewish nonneuronopathic phenotypes cannot be reliably distinguished by these inhibitor studies, and the Ashkenazi Jewish form of Gaucher disease type 1 results from a unique mutation in a specific active site domain of acid .beta.-glucosidase that leads to a defective enzyme with a decreased Vmax.