TY - JOUR
T1 - Intracisternal A-particle element transposition into the murine β- glucuronidase gene correlates with loss of enzyme activity
T2 - A new model for β-glucuronidase deficiency in the C3H mouse?
AU - Gwynn, Babette
AU - Lueders, Kira
AU - Sands, Mark S.
AU - Birkenmeier, Edward H.
PY - 1998/11
Y1 - 1998/11
N2 - The severity of human mucopolysaccharidosis type VII (MPS VII), or Sly syndrome, depends on the relative activity of the enzyme β-glucuronidase. Loss of β-glucuronidase activity can cause hydrops fetalis, with in utero or postnatal death of the patient. In this report, we show that β-glucuronidase activity is not detectable by a standard fluorometric assay in C3H/HeOuJ (C3H) mice homozygous for a new mutation, gus(mps2J). These gus(mps2J)/gus(mps2J) mice are born and survive much longer than the previously characterized β-glucuronidase-null B6.C-H-2(bm1)/ByBir-gus(mps) (gus(mps)/gus(mps)) mice. Northern blot analysis of liver from gus(mps2J)/gus(mps2J) mice demonstrates a 750-bp reduction in size of β- glucuronidase mRNA. A 5.4-kb insertion in the Gus-s(h) 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 β-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 gus(mps)/gus(mps) mouse and provides an opportunity to study MPS VII on a genetic background that clearly modulates disease severity.
AB - The severity of human mucopolysaccharidosis type VII (MPS VII), or Sly syndrome, depends on the relative activity of the enzyme β-glucuronidase. Loss of β-glucuronidase activity can cause hydrops fetalis, with in utero or postnatal death of the patient. In this report, we show that β-glucuronidase activity is not detectable by a standard fluorometric assay in C3H/HeOuJ (C3H) mice homozygous for a new mutation, gus(mps2J). These gus(mps2J)/gus(mps2J) mice are born and survive much longer than the previously characterized β-glucuronidase-null B6.C-H-2(bm1)/ByBir-gus(mps) (gus(mps)/gus(mps)) mice. Northern blot analysis of liver from gus(mps2J)/gus(mps2J) mice demonstrates a 750-bp reduction in size of β- glucuronidase mRNA. A 5.4-kb insertion in the Gus-s(h) 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 β-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 gus(mps)/gus(mps) mouse and provides an opportunity to study MPS VII on a genetic background that clearly modulates disease severity.
UR - http://www.scopus.com/inward/record.url?scp=0031770826&partnerID=8YFLogxK
U2 - 10.1128/mcb.18.11.6474
DO - 10.1128/mcb.18.11.6474
M3 - Article
C2 - 9774663
AN - SCOPUS:0031770826
SN - 0270-7306
VL - 18
SP - 6474
EP - 6481
JO - Molecular and cellular biology
JF - Molecular and cellular biology
IS - 11
ER -