Kaartinen V, Mononen I, Voncken J W, Noronkoski T, Gonzalez-Gomez I, Heisterkamp N, Groffen J
Department of Pathology, Childrens Hospital of Los Angeles Research Institute, California 90027, USA.
Nat Med. 1996 Dec;2(12):1375-8. doi: 10.1038/nm1296-1375.
Aspartylglycosaminuria (AGU), the most common disorder of glycoprotein degradation in humans, is caused by mutations in the gene encoding the lysosomal enzyme glycosylasparaginase (Aga). The resulting enzyme deficiency allows aspartylglucosamine (GlcNAc-Asn) and other glycoasparagines to accumulate in tissues and body fluids, from early fetal life onward. The clinical course is characterized by normal early development, slowly progressing to severe mental and motor retardation in early adulthood. The exact pathogenesis of AGU in humans is unknown and neither therapy nor an animal model for this debilitating and ultimately fatal disease exists. Through targeted disruption of the mouse Aga gene in embryonic stem cells, we generated mice that completely lack Aga activity. At the age of 5-10 months a massive accumulation of GlcNAc-Asn was detected along with lysosomal vacuolization, axonal swelling in the gracile nucleus and impaired neuromotor coordination. A significant number of older male mice had massively swollen bladders, which was not caused by obstruction, but most likely related to the impaired function of the nervous system. These findings are consistent with the pathogenesis of AGU and provide further data explaining the impaired neurological function in AGU patients.
天冬氨酰氨基葡糖苷酶缺乏症（AGU）是人类最常见的糖蛋白降解障碍疾病，由编码溶酶体酶糖基天冬酰胺酶（Aga）的基因突变引起。由此产生的酶缺乏会导致天冬氨酰葡糖胺（GlcNAc-Asn）和其他糖天冬酰胺从胎儿早期开始就在组织和体液中蓄积。临床病程的特点是早期发育正常，在成年早期逐渐发展为严重的智力和运动发育迟缓。人类AGU的确切发病机制尚不清楚，目前既没有针对这种使人衰弱并最终致命疾病的治疗方法，也没有动物模型。通过在胚胎干细胞中靶向破坏小鼠Aga基因，我们培育出了完全缺乏Aga活性的小鼠。在5至10个月大时，检测到大量GlcNAc-Asn蓄积，同时伴有溶酶体空泡化、薄束核轴突肿胀和神经运动协调受损。相当数量的老年雄性小鼠膀胱严重肿胀，这并非由梗阻引起，很可能与神经系统功能受损有关。这些发现与AGU的发病机制一致，并为解释AGU患者神经功能受损提供了更多数据。
