α-Galactosidase A deficient mice: A model of fabry disease

Toshio Ohshima, Gary J. Murray, William D. Swaim, Glenn Longenecker, Jane M. Quirk, Carol O. Cardarelli, Yoshikazu Sugimoto, Ira Pastan, Michael M. Gottesman, Roscoe O. Brady, Ashok B. Kulkarni

Research output: Contribution to journalArticle

244 Citations (Scopus)

Abstract

Fabry disease is an X-linked inherited metabolic disorder that is caused by a deficiency of α-galactosidase A (α-Gal A). Progressive deposition of neutral glycosphingolipids that have terminal α-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 α-Gal A deficient mice by gene targeting and an analysis of the resulting phenotype. The knockout mice display a complete lack of α-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 α-D-galactosyl residues showed accumulation of substrate in the kidneys as well 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 α-Gal A activity and the accumulation of material containing terminal α-galactosyl residues in cultured embryonic fibroblasts derived from α-Gal A (-/0) mice were corrected by transducing these cells with bicistronic multidrug resistance retroviruses containing human α-Gal A cDNA.

Original languageEnglish
Pages (from-to)2540-2544
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume94
Issue number6
DOIs
Publication statusPublished - 1997 Mar 18
Externally publishedYes

Fingerprint

Galactosidases
Fabry Disease
Kidney
Neutral Glycosphingolipids
Fibroblasts
Gene Targeting
Multiple Drug Resistance
Retroviridae
Lectins
Knockout Mice
Confocal Microscopy
Renal Insufficiency
Endothelial Cells
Animal Models
Complementary DNA
Stroke
Myocardial Infarction
Phenotype
Lipids
Liver

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Ohshima, T., Murray, G. J., Swaim, W. D., Longenecker, G., Quirk, J. M., Cardarelli, C. O., ... Kulkarni, A. B. (1997). α-Galactosidase A deficient mice: A model of fabry disease. Proceedings of the National Academy of Sciences of the United States of America, 94(6), 2540-2544. https://doi.org/10.1073/pnas.94.6.2540

α-Galactosidase A deficient mice : A model of fabry disease. / Ohshima, Toshio; Murray, Gary J.; Swaim, William D.; Longenecker, Glenn; Quirk, Jane M.; Cardarelli, Carol O.; Sugimoto, Yoshikazu; Pastan, Ira; Gottesman, Michael M.; Brady, Roscoe O.; Kulkarni, Ashok B.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 94, No. 6, 18.03.1997, p. 2540-2544.

Research output: Contribution to journalArticle

Ohshima, T, Murray, GJ, Swaim, WD, Longenecker, G, Quirk, JM, Cardarelli, CO, Sugimoto, Y, Pastan, I, Gottesman, MM, Brady, RO & Kulkarni, AB 1997, 'α-Galactosidase A deficient mice: A model of fabry disease', Proceedings of the National Academy of Sciences of the United States of America, vol. 94, no. 6, pp. 2540-2544. https://doi.org/10.1073/pnas.94.6.2540
Ohshima, Toshio ; Murray, Gary J. ; Swaim, William D. ; Longenecker, Glenn ; Quirk, Jane M. ; Cardarelli, Carol O. ; Sugimoto, Yoshikazu ; Pastan, Ira ; Gottesman, Michael M. ; Brady, Roscoe O. ; Kulkarni, Ashok B. / α-Galactosidase A deficient mice : A model of fabry disease. In: Proceedings of the National Academy of Sciences of the United States of America. 1997 ; Vol. 94, No. 6. pp. 2540-2544.
@article{ef8cbfa76ef64bc8a6f63b42f2ea8da6,
title = "α-Galactosidase A deficient mice: A model of fabry disease",
abstract = "Fabry disease is an X-linked inherited metabolic disorder that is caused by a deficiency of α-galactosidase A (α-Gal A). Progressive deposition of neutral glycosphingolipids that have terminal α-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 α-Gal A deficient mice by gene targeting and an analysis of the resulting phenotype. The knockout mice display a complete lack of α-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 α-D-galactosyl residues showed accumulation of substrate in the kidneys as well 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 α-Gal A activity and the accumulation of material containing terminal α-galactosyl residues in cultured embryonic fibroblasts derived from α-Gal A (-/0) mice were corrected by transducing these cells with bicistronic multidrug resistance retroviruses containing human α-Gal A cDNA.",
author = "Toshio Ohshima and Murray, {Gary J.} and Swaim, {William D.} and Glenn Longenecker and Quirk, {Jane M.} and Cardarelli, {Carol O.} and Yoshikazu Sugimoto and Ira Pastan and Gottesman, {Michael M.} and Brady, {Roscoe O.} and Kulkarni, {Ashok B.}",
year = "1997",
month = "3",
day = "18",
doi = "10.1073/pnas.94.6.2540",
language = "English",
volume = "94",
pages = "2540--2544",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "6",

}

TY - JOUR

T1 - α-Galactosidase A deficient mice

T2 - A model of fabry disease

AU - Ohshima, Toshio

AU - Murray, Gary J.

AU - Swaim, William D.

AU - Longenecker, Glenn

AU - Quirk, Jane M.

AU - Cardarelli, Carol O.

AU - Sugimoto, Yoshikazu

AU - Pastan, Ira

AU - Gottesman, Michael M.

AU - Brady, Roscoe O.

AU - Kulkarni, Ashok B.

PY - 1997/3/18

Y1 - 1997/3/18

N2 - Fabry disease is an X-linked inherited metabolic disorder that is caused by a deficiency of α-galactosidase A (α-Gal A). Progressive deposition of neutral glycosphingolipids that have terminal α-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 α-Gal A deficient mice by gene targeting and an analysis of the resulting phenotype. The knockout mice display a complete lack of α-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 α-D-galactosyl residues showed accumulation of substrate in the kidneys as well 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 α-Gal A activity and the accumulation of material containing terminal α-galactosyl residues in cultured embryonic fibroblasts derived from α-Gal A (-/0) mice were corrected by transducing these cells with bicistronic multidrug resistance retroviruses containing human α-Gal A cDNA.

AB - Fabry disease is an X-linked inherited metabolic disorder that is caused by a deficiency of α-galactosidase A (α-Gal A). Progressive deposition of neutral glycosphingolipids that have terminal α-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 α-Gal A deficient mice by gene targeting and an analysis of the resulting phenotype. The knockout mice display a complete lack of α-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 α-D-galactosyl residues showed accumulation of substrate in the kidneys as well 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 α-Gal A activity and the accumulation of material containing terminal α-galactosyl residues in cultured embryonic fibroblasts derived from α-Gal A (-/0) mice were corrected by transducing these cells with bicistronic multidrug resistance retroviruses containing human α-Gal A cDNA.

UR - http://www.scopus.com/inward/record.url?scp=12644284502&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=12644284502&partnerID=8YFLogxK

U2 - 10.1073/pnas.94.6.2540

DO - 10.1073/pnas.94.6.2540

M3 - Article

C2 - 9122231

AN - SCOPUS:12644284502

VL - 94

SP - 2540

EP - 2544

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 6

ER -