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

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. Results Tissue distribution of mouse GBA2.A full-length cDNA encoding the mouse GBA2 enzyme was isolated by RT-PCR from liver mRNA.Conceptual translation of the cDNA sequence predicted a protein of 918 amino acids with 83% sequence identity to the previously Nonstandard abbreviations used: DAZL, deleted in Azoospermia-like; GBA1, β-glucosidase acid 1; GBA2, β-glucosidase 2. Conflict of interest:The authors have declared that no conflict of interest exists.