Increased globotriaosylceramide levels in a transgenic mouse expressing human alpha1,4-galactosyltransferase and a mouse model for treating Fabry disease.
Fabry disease is a lysosomal storage disorder caused by an α-galactosidase A (α-Gal A) deficiency and resulting in the accumulation of glycosphingolipids, predominantly globotriaosylceramide (Gb3). A transgenic mouse expressing the human α-Gal A R301Q mutant in an α-Gal A-knockout background (TgM/KO) should be useful for studying active-site-specific chaperone (ASSC) therapy for Fabry disease. However, the Gb3 content in the heart tissue of this mouse was too low to detect an ASSC-induced effect. To increase the Gb3 levels in mouse organs, we created transgenic mice (TgG3S) expressing human α1,4-galactosyltransferase (Gb3 synthase). High levels of Gb3 were observed in all major organs of the TgG3S mouse. A TgG3S (+/-)M(+/-)/KO mouse was prepared by cross-breeding the TgG3S and TgM/KO mice and the Gb3 content in the heart of the TgG3S(+/-)M(+/-)/KO mouse was 1.4 µg/mg protein, higher than in the TgM(+/-)/KO (<0.1 µg/mg protein). Treatment with an ASSC, 1-deoxygalactonojirimycin, caused a marked induction of α-Gal A activity and a concomitant reduction of the Gb3 content in the TgG3S(+/-) M(+/-)/KO mouse organs. These data indicated that the TgG3S(+/-) M(+/-)/KO mouse was suitable for studying ASSC therapy for Fabry disease, and that the TgG3S mouse would be useful for studying the effect of high Gb3 levels in mouse organs.
Department of Agricultural and Life Sciences, Obihiro University of Agriculture and Veterinary Medicine, Obihiro, Hokkaido, Japan.
Chikara
C
Shiozuka
Atsumi
A
Taguchi
Junichiro
J
Matsuda
Yoko
Y
Noguchi
Takanori
T
Kunieda
Kozue
K
Uchio-Yamada
Hidekatsu
H
Yoshioka
Ryoji
R
Hamanaka
Shinji
S
Yano
Shigeo
S
Yokoyama
Kazuaki
K
Mannen
Ashok B
AB
Kulkarni
Koichi
K
Furukawa
Satoshi
S
Ishii
D017485:1-Deoxynojirimycin / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D003433:Crosses, Genetic; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects; D000795:Fabry Disease / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics; D005260:Female; D005700:Galactosyltransferases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007668:Kidney / Q000737:chemistry; D008099:Liver / Q000737:chemistry; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018832:Molecular Chaperones / Q000494:pharmacology; D013154:Spleen / Q000737:chemistry; D014281:Trihexosylceramides / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects; D000519:alpha-Galactosidase / Q000235:genetics / Q000378:metabolism*
D018832:Molecular Chaperones; D014281:Trihexosylceramides; D017485:1-Deoxynojirimycin; C018549:globotriaosylceramide; C090092:migalastat; D005700:Galactosyltransferases; C045097:UDP-galactose-lactosylceramide alpha 1-4-galactosyltransferase; D000519:alpha-Galactosidase