title: Transgenic mice expressing human glucocerebrosidase variants: utility for the study of Gaucher disease.
abstract: Gaucher disease is an autosomal recessively inherited storage disorder caused by deficiency of the lysosomal hydrolase, acid β-glucosidase. The disease manifestations seen in Gaucher patients are highly heterogeneous as is the responsiveness to therapy. The elucidation of the precise factors responsible for this heterogeneity has been challenging as the development of clinically relevant animal models of Gaucher disease has been problematic. Although numerous murine models for Gaucher disease have been described each has limitations in their specific utility. We describe here, transgenic murine models of Gaucher disease that will be particularly useful for the study of pharmacological chaperones. We have produced stable transgenic mouse strains that individually express wild type, N370S and L444P containing human acid β-glucosidase and show that each of these transgenic lines rescues the lethal phenotype characteristic of acid β-glucosidase null mice. Both the N370S and L444P transgenic models show early and progressive elevations of tissue sphingolipids with L444P mice developing progressive splenic Gaucher cell infiltration. We demonstrate the potential utility of these new transgenic models for the study of Gaucher disease pathogenesis. In addition, since these mice produce only human enzyme, they are particularly relevant for the study of pharmacological chaperones that are specifically targeted to human acid β-glucosidase and the common mutations underlying Gaucher disease.
authors: Department of Medical Genetics, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada.
authors: Angela
authors: A
authors: Sanders
authors: Harmony
authors: H
authors: Hemmelgarn
authors: Heather L
authors: HL
authors: Melrose
authors: Leanne
authors: L
authors: Hein
authors: Maria
authors: M
authors: Fuller
authors: Lorne A
authors: LA
authors: Clarke
mesh_terms: D000551:Ambroxol / Q000494:pharmacology; D000818:Animals; D002531:Cerebellum / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D005776:Gaucher Disease / Q000201:enzymology* / Q000235:genetics*; D015870:Gene Expression; D014644:Genetic Variation; D005838:Genotype; D005962:Glucosylceramidase / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D050112:Imino Pyranoses / Q000494:pharmacology; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D010641:Phenotype; D013154:Spleen / Q000378:metabolism / Q000473:pathology
chemical_list: D050112:Imino Pyranoses; C098432:isofagomine; D000551:Ambroxol; D005962:Glucosylceramidase