Hh. Li et al., Mouse model of Sanfilippo syndrome type B produced by targeted disruption of the gene encoding alpha-N-acetylglucosaminidase, P NAS US, 96(25), 1999, pp. 14505-14510
Citations number
40
Categorie Soggetti
Multidisciplinary
Journal title
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
The Sanfilippo syndrome type B is an autosomal recessive disorder caused by
mutation in the gene (NAGLU) encoding alpha-N-acetylglucosaminidase, a lys
osomal enzyme required for the stepwise degradation of heparan sulfate. The
most serious manifestations are profound mental retardation, intractable b
ehavior problems, and death in the second decade. To generate a model for s
tudies of pathophysiology and of potential therapy, we disrupted exon 6 of
Naglu, the homologous mouse gene. Naglu-/- mice were healthy and fertile wh
ile young and could survive for 8-12 mo. They were totally deficient in alp
ha-N-acetylglucosaminidase and had massive accumulation of heparan sulfate
in liver and kidney as well as secondary changes in activity of several oth
er lysosomal enzymes in liver and brain and elevation of gangliosides G(M2)
and G(M3) in brain. Vacuolation was seen in many cells, including macropha
ges, epithelial cells, and neurons, and became more prominent with age. Alt
hough most vacuoles contained finely granular material characteristic of gl
ycosaminoglycan accumulation, large pleiomorphic inclusions were seen in so
me neurons and pericytes in the brain. Abnormal hypoactive behavior was man
ifested by 4.5-mo-old Naglu-/- mice in an open field test; the hyperactivit
y that is characteristic of affected children was not observed even in youn
ger 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 attributabl
e to hearing impairment. The phenotype of the alpha-N-acetylglucosaminidase
-deficient mice is sufficiently similar to that of patients with the Sanfil
ippo syndrome type B to make these mice a good model for study of pathophys
iology and for development of therapy.