We describe the clinical and pathologic findings in a murine model of
mucopolysaccharidosis VII (
Sly disease) that arose spontaneously in the C3H/HeOuJ mouse strain. Affected gus(mps2J)/gus(mps2J) mice are deficient in
beta-glucuronidase because of insertion of an intracisternal A particle element into intron 8 of the gus structural gene. This is the first model of a human
lysosomal storage disease caused by an intracisternal A particle element insertion. Mice with the gus(mps2J)/gus(mps2J) genotype have < 1% of normal
beta-glucuronidase activity and secondary elevations of other lysosomal
enzymes. The phenotype includes shortened life-span, dysmorphic features, and skeletal dysplasia. Lysosomal storage of
glycosaminoglycans is widespread and affects the brain, skeleton, eye, ear, heart valves, aorta, and the fixed tissue macrophage system. Thus the phenotypic and pathologic alterations in gus(mps2J)/gus(mps2J) mice are similar to those in patients with
mucopolysaccharidosis VII. The finding of
antibodies to
beta-glucuronidase in some older gus(mps2J)/gus(mps2J) mice suggests the mice produce sufficient
enzyme to elicit an immune response. The gus(mps2J)/gus(mps2J) model provides another well-defined genetic system for the study of the pathophysiology of
mucopolysaccharidosis and for evaluation of
experimental therapies for
lysosomal storage diseases. The disease in gus(mps2J)/gus(mps2J) mice is less severe than that seen in the previously characterized B6.C-H2(bm1)/ByBir-gus(mps)/gus(mps) mouse model. Furthermore, unlike gus(mps)/gus(mps) mice, gus(mps2J)/gus(mps2J) mice are fertile and breed to produce litters, all of which are
mucopolysaccharidosis VII pups. This feature makes them extremely useful for testing intrauterine
therapies.