Faculty Research 1990 - 1999

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.

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beta-N-Acetylhexosaminidase: an, Animal, Base-Sequence, Disease-Models-Animal, DNA-Mutational-Analysis, Genes-Intracisternal-A-Particle: ge, Genotype, Glucuronidase: df, Human, Liver: en, pa, Lysosomes: en, pa, Mice, Mice-Inbred-Strains, Molecular-Sequence-Data, Mucopolysaccharidosis-VII: ge, Mutagenesis-Insertional: ge, Phenotype, Polymerase-Chain-Reaction, RNA-Messenger: an, SUPPORT-U-S-GOVT-P-H-S

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Mol Cell Biol 1998 Nov;18(11):6474-81




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, gusmps2J. These gusmps2J/gusmps2J mice are born and survive much longer than the previously characterized beta-glucuronidase-null B6.C-H-2(bm1)/ByBir-gusmps (gusmps/gusmps) mice. Northern blot analysis of liver from gusmps2J/gusmps2J mice demonstrates a 750-bp reduction in size of beta-glucuronidase mRNA. A 5.4-kb insertion in the Gus-sh 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 beta-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 gusmps/gusmps mouse and provides an opportunity to study MPS VII on a genetic background that clearly modulates disease severity.

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