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Animal model of Gaucher's disease from targeted disruption of the mouse glucocerebrosidase gene

Abstract

GAUCHER'S disease is the most prevalent lysosomal storage disorder in humans and results from an autosomally inherited deficiency of the enzyme glucocerebrosidase (β-D-glucosyl-N-acylsphingosine glucohydrolase)1–6, which is responsible for degrading the sphingolipid glucocerebroside. An animal model for Gaucher's disease would be important for investigating its phenorypic diversity and pathogenesis and for evaluating therapeutic approaches. A naturally occurring canine model has been reported but not propagated7. Attempts to mimic the disease in animals by inhibiting glucocerebrosidase have been inadequate8. Here we generate an animal model for Gaucher's disease by creating a null allele in embryonic stem cells through gene targeting and using these genetically modified cells to establish a mouse strain carrying the mutation9,10. Mice homozygous for this mutation have <4% of normal glucocerebrosidase activity, die within twenty-four hours of birth and store glucocerebroside in lysosomes of cells of the reticuloendothelial system.

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Tybulewicz, V., Tremblay, M., LaMarca et al. Animal model of Gaucher's disease from targeted disruption of the mouse glucocerebrosidase gene. Nature 357, 407–410 (1992). https://doi.org/10.1038/357407a0

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