Targeted disruption of the acid α-glucosidase gene in mice causes an illness with critical features of both infantile and adult human glycogen storage disease type II
Targeted disruption of the acid α-glucosidase gene in mice causes an illness with critical features of both infantile and adult human glycogen storage disease type II
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DOI：
10.1074/jbc.273.30.19086
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发表时间：
1998-07-24
影响因子：
4.8
通讯作者：
Plotz, P
中科院分区：
文献类型：
--
作者：
Raben, N;Nagaraju, K;Plotz, P
我们已经使用基因靶向来创建糖原累积病II型的小鼠模型，这是一种在不同年龄存在不同临床表型的疾病。与严重的人类婴儿疾病（庞贝氏症）一样，酸性α-葡糖苷酶基因（6（neo）/6（neo））破坏纯合子小鼠缺乏酶活性，并且开始在3周龄时在心肌和骨骼肌溶酶体中积累糖原，此后逐渐增加。到3.5周龄时，这些小鼠的活动性和力量明显降低。然而，它们正常生长，达到成年期，保持生育能力，并且，如在人类成人疾病中，老年小鼠在横膈膜中积累糖原。到8-9个月大时，动物会出现明显的肌肉萎缩和虚弱的蹒跚步态。因此，该模型以适合于评估酶或基因替代的速度概括了婴儿和成人形式的疾病的关键特征。相比之下，在第二种模型中，缺失外显子6的突变小鼠（Δ 6/Δ 6），如最近公开的具有外显子13破坏的酸性Cu-葡糖苷酶敲除（Bijvoet，A. G.，货车de Kamp，E. H、Kroos，M.，丁俊晖，杨，B。Z.，Visser，P.，巴克角E、Verbeet，M. P.，奥斯特拉，B。A.、Reuser，A.杰杰，和货车der Ploeg，A. T.（1998年）梅尔. h Genet. 7，53-62），尽管有不可区分的生化和病理变化，但具有未受损的力量和活动性（长达6.5月龄）。小鼠品系的遗传背景似乎有助于三种模型之间的差异。
We have used gene targeting to create a mouse model of glycogen storage disease type II, a disease in which distinct clinical phenotypes present at different ages. As in the severe human infantile disease (Pompe Syndrome), mice homozygous for disruption of the acid alpha-glucosidase gene (6(neo)/6(neo)) lack enzyme activity and begin to accumulate glycogen in cardiac and skeletal muscle lysosomes by 3 weeks of age, with a progressive increase thereafter. By 3.5 weeks of age, these mice have markedly reduced mobility and strength. They grow normally, however, reach adulthood, remain fertile, and, as in the human adult disease, older mice accumulate glycogen in the diaphragm. By 8-9 months of age animals develop obvious muscle wasting and a weak, waddling gait. This model, therefore, recapitulates critical features of both the infantile and the adult forms of the disease at a pace suitable for the evaluation of enzyme or gene replacement. In contrast, in a second model, mutant mice with deletion of exon 6 (Delta 6/Delta 6), like the recently published acid cu-glucosidase knockout with disruption of exon 13 (Bijvoet, A. G., van de Kamp, E. H., Kroos, M., Ding, J. H., Yang, B. Z., Visser, P., Bakker, C. E., Verbeet, M. P., Oostra, B. A., Reuser, A. J. J., and van der Ploeg, A. T. (1998) Hum. Mel. Genet. 7, 53-62), have unimpaired strength and mobility (up to 6.5 months of age) despite indistinguishable biochemical and pathological changes. The genetic background of the mouse strains appears to contribute to the differences among the three models.