title: Ubiquitous transgene expression of the glucosylceramide-synthesizing enzyme accelerates glucosylceramide accumulation and storage cells in a Gaucher disease mouse model.
abstract: Gaucher disease is a lysosomal storage disease caused by defective activity of acid β-glucosidase (GCase), which leads to the accumulation of its major substrates, glucosylceramide (GlcCer) and glucosylsphingosine (GlcSph) in many cells. To modulate cellular substrate concentration in viable mouse models of Gaucher disease (Gba1 mutants), a novel mouse model was created with enhanced glycosphingolipid biosynthesis. This was accomplished by cross-breeding Gba1 mutant mice with mice expressing a transgene (GCStg) containing the mouse glucosylceramide synthase (GCS, Ugcg) cDNA driven by the ROSA promoter, yielding GCStg/Gba1 mice. The GCStg rescued Ugcg null mice from embryonic lethality. GCStg/Gba1 mice showed 2-3 fold increases in tissue GCS activity as well as accelerated GlcCer accumulation and the appearance of lipid-laden CD68 positive macrophages in visceral organs. Although GlcCer/GlcSph concentrations were elevated in the brain, there was no neurodegenerative phenotype up to 1 yr of age conceivably due to the greater residual GCase hydrolytic activity in the brains than in the visceral tissues of 9V/null mice. These studies provide 'proof of principle' for threshold substrate flux that modifies phenotypic development in Gaucher disease and other lysosomal storage diseases.
authors.affiliation: The Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America.
authors.forename: Sonya
authors.initials: S
authors.lastname: Barnes
authors.affiliation: The Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America; The Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States of America.
authors.forename: You-Hai
authors.initials: YH
authors.lastname: Xu
authors.affiliation: The Division of Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America.
authors.forename: Wujuan
authors.initials: W
authors.lastname: Zhang
authors.affiliation: The Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Liou
authors.affiliation: The Division of Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America; The Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States of America.
authors.forename: Kenneth D R
authors.initials: KD
authors.lastname: Setchell
authors.affiliation: Dartmouth-Hitchcock Medical Center, Geisel School of Medicine, Dartmouth College, Lebanon, New Hampshire, United States of America.
authors.forename: Liming
authors.initials: L
authors.lastname: Bao
authors.affiliation: The Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America; Synageva BioPharma Corp., Lexington, Massachusetts, United States of America.
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Grabowski
authors.affiliation: The Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America; The Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States of America.
authors.forename: Ying
authors.initials: Y
authors.lastname: Sun
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D004195:Disease Models, Animal; D005776:Gaucher Disease / Q000201:enzymology* / Q000473:pathology; D005962:Glucosylceramidase / Q000096:biosynthesis / Q000235:genetics*; D005963:Glucosylceramides / Q000096:biosynthesis* / Q000378:metabolism; D005964:Glucosyltransferases / Q000235:genetics*; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic / Q000235:genetics; D000097382:CD68 Molecule
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D005962:Glucosylceramidase; D005963:Glucosylceramides; D005964:Glucosyltransferases; C081026:CD68 protein, mouse; D000097382:CD68 Molecule; C023246:ceramide glucosyltransferase