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 β-glucuronidase. Loss of β-glucuronidase activity can cause hydrops fetalis, with in utero or postnatal death of the patient. In this report, we show that β-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 β-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 β- 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 (IAP) 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 β-glucuronidase activity either by interfering with 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.