alpha-Galactosidase A deficient mice: A model of Fabry disease
alpha-Galactosidase A deficient mice: A model of Fabry disease
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DOI：
10.1073/pnas.94.6.2540
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发表时间：
1997-03-18
影响因子：
11.1
通讯作者：
Kulkarni, AB
中科院分区：
文献类型：
--
作者：
Ohshima, T;Murray, GJ;Kulkarni, AB
法布里病是一种X连锁遗传性代谢紊乱疾病，由α -半乳糖苷酶A（α -Gal A）缺乏引起。在血管内皮细胞中，具有末端α -连接半乳糖基部分的中性鞘糖脂逐渐沉积，导致患有这种疾病的患者出现肾衰竭以及过早的心肌梗死和中风。目前，对于这种疾病的患者没有特定的治疗方法。这种疾病的动物模型对于探索法布里病患者的治疗策略将是有价值的。我们在此报告通过基因打靶技术产生α -Gal A缺陷小鼠以及对所产生表型的分析。基因敲除小鼠完全缺乏α -Gal A活性。然而，这些小鼠在10周龄时临床表现正常。超微结构分析显示肾脏中有同心层状包涵体，并且使用对α -D -半乳糖基残基具有特异性的荧光标记凝集素进行共聚焦显微镜检查显示，底物在肾脏以及培养的成纤维细胞中积累。脂质分析显示肝脏和肾脏中神经酰胺三己糖苷显著积累。这些发现表明突变小鼠和法布里病患者的病理生理过程相似。通过用含有人类α -Gal A cDNA的双顺反子多药耐药逆转录病毒转导来自α -Gal A（- / 0）小鼠的培养胚胎成纤维细胞，纠正了α -Gal A活性的缺乏以及含有末端α -半乳糖基残基的物质的积累。
Fabry disease is an X-linked inherited metabolic disorder that is caused by a deficiency of alpha-galactosidase A (alpha-Gal A). Progressive deposition of neutral glycosphingolipids that have terminal alpha-linked galactosyl moieties in vascular endothelial cells causes renal failure along with premature myocardial infarctions and strokes in patients with this condition, No specific treatment is available for patients with this disorder at this time, An animal model of this condition would be valuable for exploring therapeutic strategies for patients with Fabry disease, We report here the generation of alpha-Gal A deficient mice by gene targeting and an analysis of the resulting phenotype. The knockout mice display a complete lack of alpha-Gal A activity. The mice, however, appeared clinically normal at 10 weeks of age. Ultrastructural analysis revealed concentric lamellar inclusions in the kidneys, and confocal microscopy using a fluorescent-labeled lectin specific for alpha-D-galactosyl residues showed accumulation of substrate in the kidneys as web as in cultured fibroblasts, Lipid analysis revealed a marked accumulation of ceramidetrihexoside in the liver and the kidneys. These findings indicate the similarity of the pathophysiological process in the mutant mice and in patients with Fabry disease, The deficiency of alpha-Gal A activity and the accumulation of material containing terminal alpha-galactosyl residues in cultured embryonic fibroblasts derived from alpha-Gal A(-/0) mice were corrected by transducing these cells with bicistronic multidrug resistance retroviruses containing human alpha-Gal A cDNA.