PMID- 10588735
OWN - NLM
STAT- MEDLINE
DCOM- 20000105
LR  - 20190501
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 96
IP  - 25
DP  - 1999 Dec 7
TI  - Mouse model of Sanfilippo syndrome type B produced by targeted disruption of the 
      gene encoding alpha-N-acetylglucosaminidase.
PG  - 14505-10
AB  - The Sanfilippo syndrome type B is an autosomal recessive disorder caused by
      mutation in the gene (NAGLU) encoding alpha-N-acetylglucosaminidase, a lysosomal 
      enzyme required for the stepwise degradation of heparan sulfate. The most serious
      manifestations are profound mental retardation, intractable behavior problems,
      and death in the second decade. To generate a model for studies of
      pathophysiology and of potential therapy, we disrupted exon 6 of Naglu, the
      homologous mouse gene. Naglu-/- mice were healthy and fertile while young and
      could survive for 8-12 mo. They were totally deficient in
      alpha-N-acetylglucosaminidase and had massive accumulation of heparan sulfate in 
      liver and kidney as well as secondary changes in activity of several other
      lysosomal enzymes in liver and brain and elevation of gangliosides G(M2) and
      G(M3) in brain. Vacuolation was seen in many cells, including macrophages,
      epithelial cells, and neurons, and became more prominent with age. Although most 
      vacuoles contained finely granular material characteristic of glycosaminoglycan
      accumulation, large pleiomorphic inclusions were seen in some neurons and
      pericytes in the brain. Abnormal hypoactive behavior was manifested by 4.5-mo-old
      Naglu-/- mice in an open field test; the hyperactivity that is characteristic of 
      affected children was not observed even in younger mice. In a Pavlovian fear
      conditioning test, the 4.5-mo-old mutant mice showed normal response to context, 
      indicating intact hippocampal-dependent learning, but reduced response to a
      conditioning tone, perhaps attributable to hearing impairment. The phenotype of
      the alpha-N-acetylglucosaminidase-deficient mice is sufficiently similar to that 
      of patients with the Sanfilippo syndrome type B to make these mice a good model
      for study of pathophysiology and for development of therapy.
FAU - Li, H H
AU  - Li HH
AD  - Department of Biological Chemistry, University of California, Los Angeles, CA
      90095, USA.
FAU - Yu, W H
AU  - Yu WH
FAU - Rozengurt, N
AU  - Rozengurt N
FAU - Zhao, H Z
AU  - Zhao HZ
FAU - Lyons, K M
AU  - Lyons KM
FAU - Anagnostaras, S
AU  - Anagnostaras S
FAU - Fanselow, M S
AU  - Fanselow MS
FAU - Suzuki, K
AU  - Suzuki K
FAU - Vanier, M T
AU  - Vanier MT
FAU - Neufeld, E F
AU  - Neufeld EF
LA  - eng
SI  - GENBANK/AF003255
GR  - F32 NS010141/NS/NINDS NIH HHS/United States
GR  - R01 NS022376/NS/NINDS NIH HHS/United States
GR  - NS 10141/NS/NINDS NIH HHS/United States
GR  - NS 22376/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (Gangliosides)
RN  - 0 (Glycosaminoglycans)
RN  - 9050-30-0 (Heparitin Sulfate)
RN  - EC 3.2.1.50 (alpha-N-acetyl-D-glucosaminidase)
RN  - EC 3.2.1.52 (Acetylglucosaminidase)
SB  - IM
MH  - Acetylglucosaminidase/*genetics
MH  - Animals
MH  - Base Sequence
MH  - Behavior, Animal
MH  - Brain Chemistry
MH  - *Disease Models, Animal
MH  - Female
MH  - Gangliosides/analysis
MH  - Glycosaminoglycans/metabolism
MH  - Heparitin Sulfate/metabolism
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Molecular Sequence Data
MH  - Mucopolysaccharidosis III/*etiology/metabolism/pathology
PMC - PMC24466
EDAT- 1999/12/10 00:00
MHDA- 1999/12/10 00:01
CRDT- 1999/12/10 00:00
PHST- 1999/12/10 00:00 [pubmed]
PHST- 1999/12/10 00:01 [medline]
PHST- 1999/12/10 00:00 [entrez]
AID - 10.1073/pnas.96.25.14505 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 1999 Dec 7;96(25):14505-10. doi:
      10.1073/pnas.96.25.14505.