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.