TY - JOUR
T1 - α-Galactosidase A knockout mice
T2 - Progressive organ pathology resembles the type 2 later-onset phenotype of fabry disease
AU - Bangari, Dinesh S.
AU - Ashe, Karen M.
AU - Desnick, Robert J.
AU - Maloney, Colleen
AU - Lydon, John
AU - Piepenhagen, Peter
AU - Budman, Eva
AU - Leonard, John P.
AU - Cheng, Seng H.
AU - Marshall, John
AU - Thurberg, Beth L.
N1 - Publisher Copyright:
© 2015 American Society for Investigative Pathology.
PY - 2015/3/1
Y1 - 2015/3/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84925071355&partnerID=8YFLogxK
U2 - 10.1016/j.ajpath.2014.11.004
DO - 10.1016/j.ajpath.2014.11.004
M3 - Article
C2 - 25553976
AN - SCOPUS:84925071355
SN - 0002-9440
VL - 185
SP - 651
EP - 665
JO - American Journal of Pathology
JF - American Journal of Pathology
IS - 3
ER -