Gaucher disease: expression and characterization of mild and severe acid beta-glucosidase mutations in Portuguese type 1 patients

Type 1 Gaucher disease (CD), the most prevalent lysosomal storage disease, results from the deficient activity of acid beta-glucosidase. Molecular ana lysis of 12 unrelated Portuguese patients with type 1 CD identified three n ovel acid beta-glucosidase mutations (F109V, W184R and R395P), as well as t hree previously reported, but uncharacterized, lesions (R359Q, G3775 and N3 96T). The type 1 probands were either heteroallelic for the well-characteri zed common lesion, N370S, and the F109V, W184R, R359Q or N396T lesions or h omoallelic for the C3775 or N396T mutations. Expression of the W184R, R359Q , and R395P mutations revealed very low specific activities based on cross- reacting immunologic material (CRIM SAs of 0.0004, 0.016 and 0.045, respect ively), consistent with their being found only in type 1 patients who had a neuroprotective N3705 allele. In contrast, the F109V, C3775 and N396T alle les had significant acid beta-glucosidase activity (CRIM specific activitie s of 0.15, 0.17, 0.14, respectively), in agreement with their being mild ty pe 1 alleles. Thus, these studies identified additional acid beta-glucosida se mutations in the Portuguese population and demonstrated that the G3775 a nd N396T mutations were neuroprotective, consistent with the mild clinical phenotypes of the type 1 patients who were homoallelic for the C3775 and N3 96T lesions.