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-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.
Gwynn
B
B
The Jackson Laboratory, Bar Harbor, Maine 04609, USA. bfg@artha.jax.org
Lueders
K
K
Sands
M S
MS
Birkenmeier
E H
EH
D000818:Animals; D001483:Base Sequence; D004252:DNA Mutational Analysis; D004195:Disease Models, Animal; D007426:Genes, Intracisternal A-Particle / Q000235:genetics*; D005838:Genotype; D005966:Glucuronidase / Q000172:deficiency*; D006801:Humans; D008099:Liver / Q000201:enzymology / Q000473:pathology; D008247:Lysosomes / Q000201:enzymology / Q000473:pathology; D051379:Mice; D008815:Mice, Inbred Strains; D008969:Molecular Sequence Data; D016538:Mucopolysaccharidosis VII / Q000235:genetics; D016254:Mutagenesis, Insertional / Q000235:genetics; D010641:Phenotype; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000032:analysis; D000519:alpha-Galactosidase / Q000032:analysis; D001619:beta-N-Acetylhexosaminidases / Q000032:analysis
D012333:RNA, Messenger; D000519:alpha-Galactosidase; D005966:Glucuronidase; D001619:beta-N-Acetylhexosaminidases