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Mouse model of Sanfilippo syndrome type B produced by targeted disruption of the gene encoding α- N -acetylglucosaminidase
- Source :
- Proceedings of the National Academy of Sciences. 96:14505-14510
- Publication Year :
- 1999
- Publisher :
- Proceedings of the National Academy of Sciences, 1999.
-
Abstract
- The Sanfilippo syndrome type B is an autosomal recessive disorder caused by mutation in the gene ( NAGLU ) encoding α- 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 α- 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 α- 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.
- Subjects :
- Male
medicine.medical_specialty
Molecular Sequence Data
Mutant
Context (language use)
Biology
medicine.disease_cause
Mice
Mucopolysaccharidosis III
Exon
chemistry.chemical_compound
Gangliosides
Internal medicine
Acetylglucosaminidase
medicine
Animals
Glycosaminoglycans
Sanfilippo syndrome
Brain Chemistry
Mice, Knockout
Mutation
Multidisciplinary
Base Sequence
Behavior, Animal
Heparan sulfate
Biological Sciences
medicine.disease
Phenotype
Pathophysiology
Mice, Inbred C57BL
Disease Models, Animal
Endocrinology
chemistry
Immunology
Female
Heparitin Sulfate
Subjects
Details
- ISSN :
- 10916490 and 00278424
- Volume :
- 96
- Database :
- OpenAIRE
- Journal :
- Proceedings of the National Academy of Sciences
- Accession number :
- edsair.doi.dedup.....4f43b90439b76186023df77280f42737