Glycosphingolipid and Glycoprotein Disorders Unit, Medical Genetic Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, United States.
Department of Pharmacology, University of Oxford, Oxford, United Kingdom.
Mol Genet Metab. 2023 Feb;138(2):107508. doi: 10.1016/j.ymgme.2023.107508. Epub 2023 Jan 13.
GM1 gangliosidosis is a rare lysosomal storage disorder affecting multiple organ systems, primarily the central nervous system, and is caused by functional deficiency of β-galactosidase (GLB1). Using CRISPR/Cas9 genome editing, we generated a mouse model to evaluate characteristics of the disease in comparison to GM1 gangliosidosis patients. Our Glb1 mice contain small deletions in exons 2 and 6, producing a null allele. Longevity is approximately 50 weeks and studies demonstrated that female Glb1 mice die six weeks earlier than male Glb1 mice. Gait analyses showed progressive abnormalities including abnormal foot placement, decreased stride length and increased stance width, comparable with what is observed in type II GM1 gangliosidosis patients. Furthermore, Glb1 mice show loss of motor skills by 20 weeks assessed by adhesive dot, hanging wire, and inverted grid tests, and deterioration of motor coordination by 32 weeks of age when evaluated by rotarod testing. Brain MRI showed progressive cerebellar atrophy in Glb1 mice as seen in some patients. In addition, Glb1 mice also show significantly increased levels of a novel pentasaccharide biomarker in urine and plasma which we also observed in GM1 gangliosidosis patients. Glb1 mice also exhibit accumulation of glycosphingolipids in the brain with increases in GM1 and GA1 beginning by 8 weeks. Surprisingly, despite being a null variant, this Glb1 mouse most closely models the less severe type II disease and will guide the development of new therapies for patients with the disorder.
GM1 神经节苷脂贮积症是一种罕见的溶酶体贮积病，影响多个器官系统，主要是中枢神经系统，是由β-半乳糖苷酶（GLB1）功能缺陷引起的。我们使用 CRISPR/Cas9 基因组编辑技术，生成了一种小鼠模型，用于与 GM1 神经节苷脂贮积症患者进行疾病特征比较。我们的 Glb1 小鼠在exon2 和 exon6 中存在小的缺失，产生了一个无功能的等位基因。寿命约为 50 周，研究表明，雌性 Glb1 小鼠比雄性 Glb1 小鼠早死亡六周。步态分析显示出进行性异常，包括足部位置异常、步幅缩短和步宽增加，与 II 型 GM1 神经节苷脂贮积症患者观察到的情况相似。此外，通过粘性斑点、悬挂线和倒置网格测试评估，20 周龄的 Glb1 小鼠表现出运动技能丧失，通过转棒测试评估，32 周龄时运动协调能力恶化。脑 MRI 显示 Glb1 小鼠的小脑进行性萎缩，一些患者也存在这种情况。此外，Glb1 小鼠的尿液和血浆中也显著增加了一种新型五糖生物标志物，我们在 GM1 神经节苷脂贮积症患者中也观察到了这种标志物。Glb1 小鼠的大脑中还存在神经节苷脂的积累，GM1 和 GA1 的增加从 8 周开始。令人惊讶的是，尽管这是一个无功能的变体，这种 Glb1 小鼠最接近 II 型疾病的轻度表现，将为该疾病患者的新疗法的开发提供指导。
