Hahn C N, del Pilar Martin M, Schröder M, Vanier M T, Hara Y, Suzuki K, Suzuki K, d'Azzo A
Department of Genetics, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Hum Mol Genet. 1997 Feb;6(2):205-11. doi: 10.1093/hmg/6.2.205.
Human GM1-gangliosidosis is caused by a genetic deficiency of lysosomal acid beta-galactosidase (beta-gal). The disease manifests itself either as an infantile, juvenile or adult form and is primarily a neurological disorder with progressive brain dysfunction. A mouse model lacking a functional beta-gal gene has been generated by homologous recombination and embryonic stem cell technology. Tissues from affected mice are devoid of beta-gal mRNA and totally deficient in GM1-ganglioside-hydrolyzing capacity. Storage material was already conspicuous in the brain at 3 weeks. By 5 weeks, extensive storage of periodic acid Schiff-positive material was observed in neurons throughout the brain and spinal cord. Consistent with the neuropathology, abnormal accumulation of GM1-ganglioside in the brain progressed from twice to almost five times the normal amount during the period from 3 weeks to 3.5 months. Despite the accumulation of brain GM1-ganglioside at the level equal to or exceeding that seen in gravely ill human patients, these mice show no overt clinical phenotype up to 4-5 months. However, tremor, ataxia and abnormal gait become apparent in older mice. Thus, the beta-gal-deficient mice appear to mimic closely the pathological, biochemical and clinical abnormalities of the human disease.
人类GM1神经节苷脂贮积症是由溶酶体酸性β-半乳糖苷酶（β-半乳糖苷酶）的基因缺陷引起的。该疾病表现为婴儿型、青少年型或成人型，主要是一种伴有进行性脑功能障碍的神经疾病。通过同源重组和胚胎干细胞技术构建了缺乏功能性β-半乳糖苷酶基因的小鼠模型。患病小鼠的组织中缺乏β-半乳糖苷酶mRNA，并且完全缺乏GM1神经节苷脂水解能力。在3周龄时，脑内的贮积物质就已很明显。到5周龄时，在整个脑和脊髓的神经元中观察到大量过碘酸希夫阳性物质的贮积。与神经病理学一致，在3周龄至3.5月龄期间，脑内GM1神经节苷脂的异常蓄积从正常量的两倍增加到几乎五倍。尽管脑内GM1神经节苷脂的蓄积水平等于或超过重症人类患者，但这些小鼠在4至5个月龄之前没有明显的临床表型。然而，老年小鼠会出现震颤、共济失调和异常步态。因此，β-半乳糖苷酶缺陷小鼠似乎密切模拟了人类疾病的病理、生化和临床异常。
