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Mutation of β-glucosidase 2 causes glycolipid storage disease and impaired male fertility
Yildiz Yildiz, … , Siegfried Matern, David W. Russell
Yildiz Yildiz, … , Siegfried Matern, David W. Russell
Published November 1, 2006
Citation Information: J Clin Invest. 2006;116(11):2985-2994. https://doi.org/10.1172/JCI29224.
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Research Article Reproductive biology Article has an altmetric score of 9

Mutation of β-glucosidase 2 causes glycolipid storage disease and impaired male fertility

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Abstract

β-Glucosidase 2 (GBA2) is a resident enzyme of the endoplasmic reticulum thought to play a role in the metabolism of bile acid–glucose conjugates. To gain insight into the biological function of this enzyme and its substrates, we generated mice deficient in GBA2 and found that these animals had normal bile acid metabolism. Knockout males exhibited impaired fertility. Microscopic examination of sperm revealed large round heads (globozoospermia), abnormal acrosomes, and defective mobility. Glycolipids, identified as glucosylceramides by mass spectrometry, accumulated in the testes, brains, and livers of the knockout mice but did not cause obvious neurological symptoms, organomegaly, or a reduction in lifespan. Recombinant GBA2 hydrolyzed glucosylceramide to glucose and ceramide; the same reaction catalyzed by the β-glucosidase acid 1 (GBA1) defective in subjects with the Gaucher’s form of lysosomal storage disease. We conclude that GBA2 is a glucosylceramidase whose loss causes accumulation of glycolipids and an endoplasmic reticulum storage disease.

Authors

Yildiz Yildiz, Heidrun Matern, Bonne Thompson, Jeremy C. Allegood, Rebekkah L. Warren, Denise M.O. Ramirez, Robert E. Hammer, F. Kent Hamra, Siegfried Matern, David W. Russell

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Figure 7

Glycolipid accumulation in Gba2–/– mice and subcellular localization of GBA2.

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Glycolipid accumulation in Gba2–/– mice and subcellular localization of ...
Glycolipids were visualized in the testes of 6- and 14-month-old wild-type (A and C) and knockout (B and D) mice by periodic acid Schiff staining of 8-μm sections. Arrows indicate small, intensely stained deposits of glycolipids that accumulated with age in the knockout mice. ST, seminiferous tubule. (E) The subcellular localization of GBA2 (green) was determined by immunofluorescent staining of simian COS cells. Lysosomes (red) were identified by staining with LysoTracker. (F) COS cells stained with a preimmune serum and LysoTracker. Scale bars are indicated in individual panels.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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Referenced in 9 patents
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