title: Gaucher disease: expression and characterization of mild and severe acid beta-glucosidase mutations in Portuguese type 1 patients.
abstract: Type 1 Gaucher disease (GD), the most prevalent lysosomal storage disease, results from the deficient activity of acid beta-glucosidase. Molecular analysis of 12 unrelated Portuguese patients with type 1 GD identified three novel acid beta-glucosidase mutations (F109V, W184R and R395P), as well as three previously reported, but uncharacterized, lesions (R359Q, G377S and N396T). The type 1 probands were either heteroallelic for the well-characterized common lesion, N370S, and the F109V, W184R, R359Q or N396T lesions or homoallelic for the G377S 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, respectively), consistent with their being found only in type 1 patients who had a neuroprotective N370S allele. In contrast, the F109V, G377S and N396T alleles had significant acid beta-glucosidase activity (CRIM specific activities of 0.15, 0.17, 0.14, respectively), in agreement with their being mild type 1 alleles. Thus, these studies identified additional acid beta-glucosidase mutations in the Portuguese population and demonstrated that the G377S and N396T mutations were neuroprotective, consistent with the mild clinical phenotypes of the type 1 patients who were homoallelic for the G377S and N396T lesions.
authors.affiliation: Instituto de Genética Médica Jacinto Magalhães, Unidade de Enzimologia, Porto, Portugal.
authors.forename: O
authors.initials: O
authors.lastname: Amaral
authors.forename: A
authors.initials: A
authors.lastname: Marcão
authors.forename: M
authors.initials: M
authors.lastname: Sá Miranda
authors.forename: R J
authors.initials: RJ
authors.lastname: Desnick
authors.forename: M E
authors.initials: ME
authors.lastname: Grace
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D019943:Amino Acid Substitution; D000818:Animals; D016367:Baculoviridae / Q000235:genetics; D002460:Cell Line; D002648:Child; D002675:Child, Preschool; D003511:Cyclohexanols / Q000494:pharmacology; D053138:Cyclohexenes; D004247:DNA / Q000737:chemistry / Q000235:genetics; D004252:DNA Mutational Analysis; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005776:Gaucher Disease / Q000201:enzymology / Q000235:genetics*; D015971:Gene Expression Regulation, Enzymologic; D005962:Glucosylceramidase / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D017354:Point Mutation; D018807:Polymorphism, Single-Stranded Conformational; D011174:Portugal; D011993:Recombinant Fusion Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D003511:Cyclohexanols; D053138:Cyclohexenes; D004791:Enzyme Inhibitors; D011993:Recombinant Fusion Proteins; C090988:conduritol B; D004247:DNA; D005962:Glucosylceramidase