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

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

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)2985-2994
Number of pages10
JournalJournal of Clinical Investigation
Volume116
Issue number11
DOIs
StatePublished - Nov 1 2006

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Glucosidases
Glucosylceramides
Glycolipids
Bile Acids and Salts
Endoplasmic Reticulum
Fertility
Glucosylceramidase
Lysosomal Storage Diseases
Glucose
Acrosome
Mutation
Ceramides
Enzymes
Knockout Mice
Spermatozoa
Testis
Mass Spectrometry
Head
Acids
Liver

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Yildiz, Y., Matern, H., Thompson, B., Allegood, J. C., Warren, R. L., Ramirez, D. M. O., ... Russell, D. W. (2006). Mutation of β-glucosidase 2 causes glycolipid storage disease and impaired male fertility. Journal of Clinical Investigation, 116(11), 2985-2994. https://doi.org/10.1172/JCI29224

Mutation of β-glucosidase 2 causes glycolipid storage disease and impaired male fertility. / Yildiz, Yildiz; Matern, Heidrun; Thompson, Bonne; Allegood, Jeremy C.; Warren, Rebekkah L.; Ramirez, Denise M O; Hammer, Robert E; Hamra, Franklin K; Matern, Siegfried; Russell, David W.

In: Journal of Clinical Investigation, Vol. 116, No. 11, 01.11.2006, p. 2985-2994.

Research output: Contribution to journalArticle

Yildiz, Y, Matern, H, Thompson, B, Allegood, JC, Warren, RL, Ramirez, DMO, Hammer, RE, Hamra, FK, Matern, S & Russell, DW 2006, 'Mutation of β-glucosidase 2 causes glycolipid storage disease and impaired male fertility', Journal of Clinical Investigation, vol. 116, no. 11, pp. 2985-2994. https://doi.org/10.1172/JCI29224
Yildiz Y, Matern H, Thompson B, Allegood JC, Warren RL, Ramirez DMO et al. Mutation of β-glucosidase 2 causes glycolipid storage disease and impaired male fertility. Journal of Clinical Investigation. 2006 Nov 1;116(11):2985-2994. https://doi.org/10.1172/JCI29224
Yildiz, Yildiz ; Matern, Heidrun ; Thompson, Bonne ; Allegood, Jeremy C. ; Warren, Rebekkah L. ; Ramirez, Denise M O ; Hammer, Robert E ; Hamra, Franklin K ; Matern, Siegfried ; Russell, David W. / Mutation of β-glucosidase 2 causes glycolipid storage disease and impaired male fertility. In: Journal of Clinical Investigation. 2006 ; Vol. 116, No. 11. pp. 2985-2994.
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