Mouse model of Sanfilippo syndrome type B produced by targeted disruption of the gene encoding alpha-N-acetylglucosaminidase

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.