title: Transgene produces massive overexpression of human beta -glucuronidase in mice, lysosomal storage of enzyme, and strain-dependent tumors.
abstract: beta-Glucuronidase (GUSB) is a lysosomal enzyme important in the normal step-wise degradation of glycosaminoglycans. Deficiency of GUSB causes the lysosomal storage disease mucopolysaccharidosis VII (MPS VII, Sly disease). Affected patients have widespread progressive accumulation of beta-glucuronide-containing glycosaminoglycans in lysosomes. Enzyme replacement, bone marrow transplantation, and gene therapy can correct lysosomal storage in the MPS VII mouse model. Gene therapy in MPS VII patients and animals may result in massive overexpression of GUSB in individual tissues, and the toxicity of such overexpression is incompletely investigated. To gain insight into the effect of massive overexpression of GUSB, we established 19 transgenic mouse lines, two of which expressed very high levels of human GUSB in many tissues. The founder overexpressing mice had from >100- to several thousand-fold increases in tissue and serum GUSB. The enzyme expression in most tissues decreased in subsequent generations in one line, and expression in liver and marrow fell in subsequent generations of the other. Both lines had morphologically similar widespread lysosomal storage of GUSB and secondary elevations of other lysosomal enzymes, a finding characteristic of lysosomal storage disease. One line developed tumors, and one did not. These transgenic models show that massive overexpression of a lysosomal enzyme can be associated with dramatic morphological alterations, which, at least in one of the two lines, had little clinical consequence. For the other transgenic line, the high frequency of tumor development in F(2) FVB progeny suggests that the vector used to generate the transgenic lines has an integration site-dependent potential to be oncogenic, at least in this strain background.
authors.affiliation: Department of Pathology, Saint Louis University School of Medicine, 1402 South Grand Boulevard, St. Louis, MO 63104, USA. volgerca@slu.edu
authors.forename: Carole
authors.initials: C
authors.lastname: Vogler
authors.forename: Nancy
authors.initials: N
authors.lastname: Galvin
authors.forename: Beth
authors.initials: B
authors.lastname: Levy
authors.forename: Jeffery
authors.initials: J
authors.lastname: Grubb
authors.forename: Jinxing
authors.initials: J
authors.lastname: Jiang
authors.forename: Xiao Yan
authors.initials: XY
authors.lastname: Zhou
authors.forename: William S
authors.initials: WS
authors.lastname: Sly
mesh_terms: D000818:Animals; D002460:Cell Line; D018076:DNA, Complementary / Q000378:metabolism; D005260:Female; D015316:Genetic Therapy / Q000379:methods; D005966:Glucuronidase / Q000096:biosynthesis* / Q000235:genetics* / Q000502:physiology; D007150:Immunohistochemistry; D008247:Lysosomes / Q000201:enzymology* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D016538:Mucopolysaccharidosis VII / Q000235:genetics / Q000628:therapy*; D009857:Oncogenes / Q000235:genetics; D012737:Sex Factors; D019076:Transgenes
chemical_list: D018076:DNA, Complementary; D005966:Glucuronidase