Intracisternal A-particle element transposition into the murine β-glucuronidase gene correlates with loss of enzyme activity:: a new model for β-glucuronidase deficiency in the C3H mouse

The severity of human mucopolysaccharidosis type VII (MPS VII), or Sly syndrome, depends on the relative activity of the enzyme beta-glucuronidase. Loss of beta-glucuronidase activity can cause hydrops fetalis, with in utero or postnatal death of the patient. In this report, we show that beta-glucuronidase activity is not detectable by a standard fluorometric assay in C3H/HeOuJ (C3H) mice homozygous for a new mutation, gus(mps2J). These gus(mps2J)/gus(mps2J) mice are born and survive much longer than the previously characterized beta-glucuronidase-null B6.C-H-2(bm1)/ByBir-gus(mps) (gus(mps)/gus(mps)) mice. Northern blot analysis of liver from gus(mps2J)/gus(mps2J) mice demonstrates a 750-bp reduction in size of beta-glucuronidase mRNA, A 5.4-kb insertion in the Gus-s(h) nucleotide sequence from these mice was localized by Southern blot analysis to intron 8, The ends of the inserted sequences were cloned by inverse PCR and revealed an intracisternal A-particle (LAP) element inserted near the 3' end of the intron, The sequence of the long terminal repeat (LTR) regions of the IAP most closely matches that of a composite LTR found in transposed IAPs previously identified in the C3H strain, The inserted IAP may contribute to diminished beta-glucuronidase activity either by interfering,vith transcription or by destabilizing the message. The resulting phenotype is much less severe than that previously described in the gus(mps)/gus(mps) mouse and provides an opportunity to study MPS VII on a genetic background that clearly modulates disease severity.