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

Abstract

The Sanfilippo syndrome type B is an autosomal recessive disorder caused by mutation in the gene (NAGLU) encoding ␣-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 ␣-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 GM3 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-moold 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 ␣-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.

Enzyme-Replacement Therapy from Birth Delays the Development of Behavior and Learning Problems in Mucopolysaccharidosis Type IIIA Mice

“…MPS IIIA mice exhibit widespread intracellular storage in a variety of cell types. Affected mice are also reported to store secondarily gangliosides G M2 and G M3 , a feature also reported in two MPS IIIA dog models (10,11), a knock-out MPS IIIB mouse (12), and a caprine MPS IIID model (13). At birth, MPS IIIA mice are indistinguishable from their unaffected litter mates.…”

Lysosomal accumulation of SCMAS (subunit c of mitochondrial ATP synthase) in neurons of the mouse model of mucopolysaccharidosis III B

“…Vacuolation of numerous neurons was seen throughout the brain of the MPS III B mice [6]. However, a number of additional histologic abnormalities were found in the same areas as immunoreactive SCMAS.…”

“…The mouse model of MPS III B (Naglu −/−) had been generated by targeted disruption of the mouse Naglu gene [6], and the mutant gene was placed on a C57BL/6 background by repeated backcrossing. Wild type control mice (Naglu +/+) were derived from the same colony.…”

“…There is no effective therapy, and management of this difficult disease is all that can be offered at the present time [1,3]. There are several animal models: the naturally occurring emu [4] and dog [5] models, and the mouse model generated by homologous recombination [6].…”

“…However, the situation is more complex in the brain. On the one hand, soluble heparan sulfate is barely elevated in the brain of MPS III B mice [6], and only two-fold in the brain of human patients with MPS III B [7]. On the other hand, there is major accumulation of substances that do not need the participation of α-Nacetylglucosaminidase for their metabolism.…”