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Molecular and Cellular Biology, November 1998, p. 6474-6481, Vol. 18, No. 11
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

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 Mousedagger

Babette Gwynn,1,* Kira Lueders,2 Mark S. Sands,3 and Edward H. Birkenmeier1

The Jackson Laboratory, Bar Harbor, Maine 046091; Laboratory of Biochemistry, National Cancer Institute, Bethesda, Maryland 20892-42552; and Washington University School of Medicine, St. Louis, Missouri 631103

Received 5 January 1998/Returned for modification 28 April 1998/Accepted 12 August 1998

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-2bm1/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.

* Corresponding author. Mailing address: The Jackson Laboratory, 600 Main St., Bar Harbor, ME 04609. Phone: (207) 288-6392. Fax: (207) 288-6073. E-mail: bfg{at}aretha.jax.org.

dagger This paper is dedicated to the memory of Edward Birkenmeier, a fine scientist and good friend, for whom every mutant mouse was an opportunity and every aspect of biology a joy.

Molecular and Cellular Biology, November 1998, p. 6474-6481, Vol. 18, No. 11
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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