title: α-Galactosidase A knockout mice: progressive organ pathology resembles the type 2 later-onset phenotype of Fabry disease.
abstract: Fabry disease is an X-linked lysosomal storage disease caused by deficient activity of α-galactosidase A and the resultant systemic accumulation of globotrioasylceramide (GL-3) and related glycolipids. α-Galactosidase A gene knockout (Gla KO) mice have no α-galactosidase A activity and progressively accumulate GL-3 in tissues and fluids, similarly to FD patients. The nature and temporal effects of the progressive substrate accumulation on tissue histology in these mice have not previously been characterized. Here, we report the pathology of young to old (3 to 17 months old) Gla KO mice and compare these changes with those in strain-matched control animals. Gla KO mice accumulated GL-3 in various tissues and fluids with age. Lysosomal GL-3 inclusions increased with age in multiple cell types, including renal epithelial, intestinal, and vascular smooth muscle cells, and neurons in trigeminal and dorsal root ganglia, as detected by light and electron microscopy. However, unlike the case for male FD patients with the type 1 classic phenotype, GL-3 inclusions were not detected in vascular endothelial cells or cardiomyocytes. The histological changes in Gla KO mice better resemble the type 2 later-onset phenotype observed in patients with residual α-galactosidase A activity. GL-3 accumulation in the small intestine and sensory ganglia of Gla KO mice provides a model for study of enteropathy and neuropathy in Fabry disease.
authors.affiliation: Department of Pathology, Genzyme Corporation, a Sanofi Company, Framingham, Massachusetts. Electronic address: dinesh.bangari@genzyme.com.
authors.forename: Dinesh S
authors.initials: DS
authors.lastname: Bangari
authors.affiliation: Department of Rare Diseases Science, Genzyme Corporation, a Sanofi Company, Framingham, Massachusetts.
authors.forename: Karen M
authors.initials: KM
authors.lastname: Ashe
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Desnick
authors.affiliation: Department of Pathology, Genzyme Corporation, a Sanofi Company, Framingham, Massachusetts.
authors.forename: Colleen
authors.initials: C
authors.lastname: Maloney
authors.affiliation: Department of Pathology, Genzyme Corporation, a Sanofi Company, Framingham, Massachusetts.
authors.forename: John
authors.initials: J
authors.lastname: Lydon
authors.affiliation: Department of Pathology, Genzyme Corporation, a Sanofi Company, Framingham, Massachusetts.
authors.forename: Peter
authors.initials: P
authors.lastname: Piepenhagen
authors.affiliation: Department of Rare Diseases Science, Genzyme Corporation, a Sanofi Company, Framingham, Massachusetts.
authors.forename: Eva
authors.initials: E
authors.lastname: Budman
authors.affiliation: Department of Rare Diseases Science, Genzyme Corporation, a Sanofi Company, Framingham, Massachusetts.
authors.forename: John P
authors.initials: JP
authors.lastname: Leonard
authors.affiliation: Department of Rare Diseases Science, Genzyme Corporation, a Sanofi Company, Framingham, Massachusetts.
authors.forename: Seng H
authors.initials: SH
authors.lastname: Cheng
authors.affiliation: Department of Rare Diseases Science, Genzyme Corporation, a Sanofi Company, Framingham, Massachusetts.
authors.forename: John
authors.initials: J
authors.lastname: Marshall
authors.affiliation: Department of Pathology, Genzyme Corporation, a Sanofi Company, Framingham, Massachusetts.
authors.forename: Beth L
authors.initials: BL
authors.lastname: Thurberg
mesh_terms: D000818:Animals; D002319:Cardiovascular System / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D018450:Disease Progression; D000795:Fabry Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D005260:Female; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000473:pathology*; D007668:Kidney / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000378:metabolism / Q000473:pathology*; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D000519:alpha-Galactosidase / Q000235:genetics* / Q000378:metabolism
chemical_list: D000519:alpha-Galactosidase