Mutation of β-glucosidase 2 causes glycolipid storage disease and impaired male fertility
Mutation of β-glucosidase 2 causes glycolipid storage disease and impaired male fertility
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DOI：
10.1172/jci29224
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发表时间：
2006-11-01
影响因子：
15.9
通讯作者：
Russell, David W.
中科院分区：
文献类型：
--
作者：
Yildiz, Yildiz;Matern, Heidrun;Russell, David W.
β-葡萄糖苷酶2（GBA 2）是内质网的一种常驻酶，被认为在胆汁酸-葡萄糖结合物的代谢中起作用。为了深入了解这种酶及其底物的生物学功能，我们产生了GBA 2缺陷的小鼠，发现这些动物具有正常的胆汁酸代谢。基因敲除的雄性表现出生育能力受损。精子显微镜检查发现大圆头（球形精子症）、顶体异常和运动缺陷。糖脂，经质谱鉴定为葡萄糖神经酰胺，在基因敲除小鼠的睾丸、大脑和肝脏中积累，但没有引起明显的神经系统症状、器官肿大或寿命缩短。重组GBA 2将葡糖神经酰胺水解为葡萄糖和神经酰胺;在患有戈谢氏形式的溶酶体贮积病的受试者中，由β-葡糖苷酶酸1（GBA 1）缺陷催化的相同反应。我们的结论是，GBA 2是一种葡萄糖神经酰胺酶，其损失导致积累的糖脂和内质网储存疾病。
beta-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 beta-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.