alpha-Galactosidase A deficient mice: A model of Fabry disease

被引：303

作者：

Ohshima, T

Murray, GJ

Swaim, WD

Longenecker, G

Quirk, JM

Cardarelli, CO

Sugimoto, Y

Pastan, I

Gottesman, MM

Brady, RO

Kulkarni, AB

机构：

[1] NIDR, GENE TARGETING RES & CORE FACIL, NIH, BETHESDA, MD 20892 USA

[2] NINCDS, DEV & METAB NEUROL BRANCH, NIH, BETHESDA, MD 20892 USA

[3] NIDR, CELLULAR IMAGING CORE FACIL, NIH, BETHESDA, MD 20892 USA

[4] NCI, CELL BIOL LAB, NIH, BETHESDA, MD 20892 USA

[5] NCI, MOL BIOL LAB, NIH, BETHESDA, MD 20892 USA

[6] JAPANESE FDN CANC RES, CTR CANC CHEMOTHERAPY, TOSHIMA KU, TOKYO 170, JAPAN

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 1997年 / 94卷 / 06期

关键词：

D O I：

10.1073/pnas.94.6.2540

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页码：2540 / 2544

页数：5

共 36 条

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