title: 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 (beta-D-glucosyl-N-acylsphingosine glucohydrolase), which is responsible for degrading the sphingolipid glucocerebroside. An animal model for Gaucher's disease would be important for investigating its phenotypic diversity and pathogenesis and for evaluating therapeutic approaches. A naturally occurring canine model has been reported but not propagated. Attempts to mimic the disease in animals by inhibiting glucocerebrosidase have been inadequate. 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 mutation. Mice homozygous for this mutation have less than 4% of normal glucocerebrosidase activity, die within twenty-four hours of birth and store glucocerebroside in lysosomes of cells of the reticuloendothelial system.
authors.affiliation: Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge 02142.
authors.forename: V L
authors.initials: VL
authors.lastname: Tybulewicz
authors.forename: M L
authors.initials: ML
authors.lastname: Tremblay
authors.forename: M E
authors.initials: ME
authors.lastname: LaMarca
authors.forename: R
authors.initials: R
authors.lastname: Willemsen
authors.forename: B K
authors.initials: BK
authors.lastname: Stubblefield
authors.forename: S
authors.initials: S
authors.lastname: Winfield
authors.forename: B
authors.initials: B
authors.lastname: Zablocka
authors.forename: E
authors.initials: E
authors.lastname: Sidransky
authors.forename: B M
authors.initials: BM
authors.lastname: Martin
authors.forename: S P
authors.initials: SP
authors.lastname: Huang
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology; D001921:Brain / Q000378:metabolism / Q000648:ultrastructure; D004195:Disease Models, Animal; D005260:Female; D005776:Gaucher Disease / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D005962:Glucosylceramidase / Q000172:deficiency / Q000235:genetics*; D006720:Homozygote; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism / Q000648:ultrastructure; D008247:Lysosomes / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D009154:Mutation; D013154:Spleen / Q000378:metabolism / Q000648:ultrastructure
chemical_list: D005962:Glucosylceramidase