Systemic inflammation in glucocerebrosidase-deficient mice with minimal glucosylceramide storage
Hiroki Mizukami, … , Konrad Sandhoff, Richard L. Proia
Hiroki Mizukami, … , Konrad Sandhoff, Richard L. Proia
Published May 1, 2002
Citation Information: J Clin Invest. 2002;109(9):1215-1221. https://doi.org/10.1172/JCI14530.
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Categories: Article Genetics

Systemic inflammation in glucocerebrosidase-deficient mice with minimal glucosylceramide storage

Abstract

Gaucher disease, the most common lysosomal storage disease, is caused by a deficiency of glucocerebrosidase resulting in the impairment of glucosylceramide degradation. The hallmark of the disease is the presence of the Gaucher cell, a macrophage containing much of the stored glucosylceramide found in tissues, which is believed to cause many of the clinical manifestations of the disease. We have developed adult mice carrying the Gaucher disease L444P point mutation in the glucocerebrosidase (Gba) gene and exhibiting a partial enzyme deficiency. The mutant mice demonstrate multisystem inflammation, including evidence of B cell hyperproliferation, an aspect of the disease found in some patients. However, the mutant mice do not accumulate large amounts of glucosylceramide or exhibit classic Gaucher cells in tissues.

Authors

Hiroki Mizukami, Yide Mi, Ryuichi Wada, Mari Kono, Tadashi Yamashita, Yujing Liu, Norbert Werth, Roger Sandhoff, Konrad Sandhoff, Richard L. Proia

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Figure 1

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Degradation and synthesis of glucosylceramide, and derivation of GbaL444...
Degradation and synthesis of glucosylceramide, and derivation of GbaL444P/L444P mice. (a) Pathway of glucosylceramide degradation and synthesis. Glucosylceramide synthase is encoded by the Ugcg gene. Glucocerebrosidase (known also as acid β-glucosidase) is encoded by the Gba gene. (b) Breeding scheme to derive adult GbaL444P/L444 mice. As described in Methods, heterozygous mice with the L444P mutation in the Gba gene were cross-bred with mice carrying a disrupted Ugcg allele (UgcgKO) to eventually obtain adult mice with the genotype GbaL444P/L444PUgcg+/KO. These double mutant mice were intercrossed to obtain adult mice with the genotype GbaL444P/L444PUgcg+/+.