title: Murine mucopolysaccharidosis type I: targeted disruption of the murine alpha-L-iduronidase gene.
abstract: Mucopolysaccharidosis type I (MPS I) is considered to represent the prototypical mucopolysaccharide storage disorder. Although a spectrum of severity is seen within the MPS I subgroup, Hurler syndrome represents the most severe and frequent manifestation of MPS I. We describe here the generation of a murine model for Hurler syndrome by targeted disruption of the murine Idua gene. Homozygous Idua -/- mice have no detectable alpha-L-iduronidase enzyme activity and show increased urinary glycosaminoglycan levels. Although normal appearing at birth, Idua -/- mice develop a flattened facial profile and thickening of the digits discernible by 3 weeks of age. No obvious growth deficiency nor mortality is seen within the first 20 weeks of life. Radiographs reveal anterior flaring of the ribs and thickening of the facial bones as early as 4 weeks of age with more extensive dysostosis detectable by 15 weeks of age. At 4 weeks of age, lysosomal storage is noted primarily within reticuloendothelial cells with abundant lysosomes noted in Kupffer cells, splenic sinusoidal lining cells, and glial cells. More widespread lysosomal storage is noted by 8 weeks of age in hepatocytes, chondrocytes, neurons, as well as renal tubular cells. Thus, targeted disruption of the murine Idua locus has produced a murine strain representative of the severe form of MPS I. This model should permit detailed evaluation of the pathophysiology of lysosomal storage disorders and provide a small animal model for the testing and development of enzyme replacement and gene therapy regimes.
authors.affiliation: Department of Medical Genetics, University of British Columbia, Vancouver, Canada.
authors.forename: L A
authors.initials: LA
authors.lastname: Clarke
authors.forename: C S
authors.initials: CS
authors.lastname: Russell
authors.forename: S
authors.initials: S
authors.lastname: Pownall
authors.forename: C L
authors.initials: CL
authors.lastname: Warrington
authors.forename: A
authors.initials: A
authors.lastname: Borowski
authors.forename: J E
authors.initials: JE
authors.lastname: Dimmick
authors.forename: J
authors.initials: J
authors.lastname: Toone
authors.forename: F R
authors.initials: FR
authors.lastname: Jirik
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics; D000818:Animals; D015152:Blotting, Northern; D015139:Blotting, Southern; D003001:Cloning, Molecular; D004195:Disease Models, Animal; D019066:Facies; D015870:Gene Expression; D018390:Gene Targeting; D006025:Glycosaminoglycans / Q000378:metabolism / Q000652:urine; D007068:Iduronidase / Q000172:deficiency / Q000235:genetics*; D008099:Liver / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D008059:Mucopolysaccharidosis I / Q000235:genetics*; D010641:Phenotype; D013154:Spleen / Q000473:pathology
chemical_list: D006025:Glycosaminoglycans; D007068:Iduronidase