Human Molecular Genetics, Vol 6, 503-511, Copyright © 1997 by Oxford University Press
LA Clarke, CS Russell, S Pownall, CL Warrington, A Borowski, JE Dimmick, J Toone and FR Jirik
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.
ARTICLES
Murine mucopolysaccharidosis type I: targeted disruption of the murine alpha-L-iduronidase gene
Department of Medical Genetics, University of British Columbia, Vancouver, Canada.
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