A novel model of murine mucopolysaccharidosis type VII due to an intracisternal a particle element transposition into the β-glucuronidase gene: Clinical and pathologic findings

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 β-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 β-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 β-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.