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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 51 print issues and online access
$199.00 per year
only $3.90 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Barranger, J. A. & Ginns, E. I. in The Metabolic Basis of Inherited Disease (eds Scriver, C. R., Beaudet, A. L., Sly, W. S. & Valle, D.) 1677–1698 (McGraw-Hill, New York, 1989).
Martin, B. M., Sidransky, E. & Ginns, E. I. Adv. Pediatr. 36, 277–306 (1989).
Tsuji, S. et al. New Engl. J. Med. 316, 570–575 (1987).
Tsuji, S. et al. Proc. natn. Acad. Sci. U.S.A. 85, 2349–2352 (1988).
Beutler, E., Gelbart, T., Kuhl, W., Sorge J. & West, C. Proc. natn. Acad. Sci. U.S.A. 81, 10544–10547 (1991).
Grabowski, G. A., Gatt, S. & Horowitz, M. Crit. Rev. Biochem. molec. Biol. 25, 385–414 (1991).
Hartley, W. J. & Farrow, R. R. H. in Handbook: Animal Models of Human Disease. Fasc II. (ed. Capen, C. C. et al.) Model No. 241, Registry of Comparative Pathology (Armed Forces Institute of Pathology, Washington, DC, 1982).
Kanfer, J. N., Stephens, M. C., Singh, H. & Legler, G. Prog. clin. biol. Res. 95, 627–644 (1982).
Robertson, E. in Teratocarcinomas and Embryonic Stem Cells: A Practical Approach (ed. Robertson, E. J.) 71–112 (IRL, Oxford, 1987).
Capecchi, M. R. Trends Genet. 5, 70–76 (1989).
O'Neill, R., Tokoro, T., Kozak, C. A. & Brady, R. O. Proc. Natn. Acad. Sci. U.S.A. 86, 5049–5053 (1989).
Mansour, S. L., Thomas, K. R. & Capecchi, M. R. Nature 336, 348–352 (1988).
Bradley, A. in Teratocarcinomas and Embryonic Stem Cells: A Practical Approach (ed. Robertson, E. J.) 113–151 (IRL, Oxford, 1987).
Willemsen, R. et al. Ultrastr. Path. 12, 471–478 (1988).
Lee, R. E. Prog. clin. biol. Res. 95, 177–218 (1982).
Fredrickson, D. S. & Sloan, H. R. in The Metabolic Basis of Inherited Disease (eds Stanbury, J. B., Wyngaarden, J. B. & Fredrickson, D. S.) 731–759 (McGraw-Hill, New York, 1978).
Sun, C. C., Panny, S., Combs, J. & Gutberlett, R. Path. Res. Pract. 179, 101–104 (1984).
Hooper, M. L., Hardy, K., Handyside, A., Hunter, S. & Monk, M. Nature 326, 292–294 (1987).
Kuehn, M. R., Bradley, A., Robertson, E. J. & Evans, M. J. Nature 326, 295–298 (1987).
Robertson, E., Bradley, A., Kuehn, M. & Evans, M. Nature 323, 445–448 (1986).
Tybulewicz, V. L. J., Crawford, C. E., Jackson, P. K., Bronson, R. T. & Mulligan, R. C. Cell 65, 1153–1163 (1991).
Beutler, E. & Kuhl, W. L. Lancet 1, 612–613 (1970).
Svennerholm, L., Hakansson, G., Mansson, J. E. & Nilsson, O. in Gaucher's Disease: A Century of Delineation and Research (eds Desnick, R. J. et al.) 231–252 (Liss, New York, 1982).
Kundu, S. K. in Meth. Enzym. (ed. Lowenstein, J. M.) 185–204 (Academic, New York, 1981).
Debruyn, W. C. & Denbreejen, P. Histochem. J. 8, 121–142 (1976).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
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
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/357407a0
This article is cited by
-
Lysosomal Pathogenesis of Parkinson's Disease: Insights From LRRK2 and GBA1 Rodent Models
Neurotherapeutics (2023)
-
BMP-1-induced GBA1 nuclear accumulation provokes CCN2 mRNA expression via importin-β-mediated nucleocytoplasmic pathway
Journal of Cell Communication and Signaling (2023)
-
Impact of Gba2 on neuronopathic Gaucher’s disease and α-synuclein accumulation in medaka (Oryzias latipes)
Molecular Brain (2021)
-
Parkinson’s disease pathogenesis from the viewpoint of small fish models
Journal of Neural Transmission (2018)
-
Gaucher Disease and Bone Manifestations
Calcified Tissue International (2014)
Comments
By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.