INTRACISTERNAL A-PARTICLE ELEMENT TRANSPOSITION INTO THE MURINE BETA-GLUCURONIDASE GENE CORRELATES WITH LOSS OF ENZYME-ACTIVITY - A NEW MODEL FOR BETA-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-glucuro nidase. Loss of beta-glucuronidase activity can cause hydrops fetalis, with in utero or postnatal death of the patient. In this report, we s how that beta-glucuronidase activity is not detectable by a standard f luorometric assay in C3H/HeOuJ (C3H) mice homozygous for a new mutatio n, gus(mps2J). These gus(mps2J)/gus(mps2J) mice are born and survive m uch longer than the previously characterized beta-glucuronidase-null B 6.C-H-2(bm1)/ByBir-gus(mps) (gus(mps)/gus(mps)) mice. Northern blot an alysis 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 th e Gus-s(h) nucleotide sequence from these mice was localized by Southe rn 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 lo ng terminal repeat (LTR) regions of the IAP most closely matches that of a composite LTR found in transposed IAPs previously identified in t he C3H strain, The inserted IAP may contribute to diminished beta-gluc uronidase activity either by interfering,vith transcription or by dest abilizing the message. The resulting phenotype is much less severe tha n that previously described in the gus(mps)/gus(mps) mouse and provide s an opportunity to study MPS VII on a genetic background that clearly modulates disease severity.