Intracisternal A-Particle Element Transposition into the Murine ß-Glucuronidase Gene Correlates with Loss of Enzyme Activity: a New Model for ß-Glucuronidase Deficiency in the C3H Mouse

ABSTRACTThe severity of human mucopolysaccharidosis type VII (MPS VII), or Sly syndrome, depends on the relative activity of the enzyme ß-glucuronidase. Loss of ß-glucuronidase activity can cause hydrops fetalis, with in utero or postnatal death of the patient. In this report, we show that ß-glucuronidase activity is not detectable by a standard fluorometric assay in C3H/HeOuJ (C3H) mice homozygous for a new mutation, gusmps2J. Thesegusmps2J/gusmps2Jmice are born and survive much longer than the previously characterized ß-glucuronidase-null B6.C-H-2bm1/ByBir-gusmps(gusmps/gusmps) mice. Northern blot analysis of liver fromgusmps2J/gusmps2Jmice demonstrates a 750-bp reduction in size of ß-glucuronidase mRNA. A 5.4-kb insertion in the Gus-shnucleotide 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 ß-glucuronidase activity either by interfering with transcription or by destabilizing the message. The resulting phenotype is much less severe than that previously described in thegusmps/gusmpsmouse and provides an opportunity to study MPS VII on a genetic background that clearly modulates disease severity.