MICE WITH AN ASPARTYLGLUCOSAMINURIA MUTATION SIMILAR TO HUMANS REPLICATE THE PATHOPHYSIOLOGY IN PATIENTS

Aspartyglucosaminurla (AGU) is a lysosomal storage disease with autoso mal recessive inheritance that is caused by deficient activity of aspa rtylglucosaminidase (AGA), a lysosomal enzyme belonging to the newly d escribed enzyme family of N-terminal hydrolases, An AGU mouse model wa s generated by targeted disruption of the AGA gene designed to mimic c losely one human disease mutation, These homozygous mutant mice have n o detectable AGA activity and excrete aspartylglucosamine in their uri ne, Analogously to the human disease, the affected homozygous animals showed storage in lysosomes in all analyzed tissues, including the bra in, liver, kidney and skin, and lysosomal storage was already detected in fetuses at 19 days gestation, Electron microscopic studies of brai n tissue samples demonstrated lysosomal storage vacuoles in the neuron s and glia of the neocortical and cortical regions. Magnetic resonance images (MRI) facilitating monitoring of the brains of living animals indicated cerebral atrophy and hypointensity of the deep gray matter s tructures of brain-findings similar to those observed in human patient s. AGU mice are fertile, and up to 11 months of age their movement and behavior do not differ from their age-matched littermates, However, i n the Morris water maze test, a slow worsening of performance could be seen with age, The phenotype mimics well AGU in humans, the patients characteristically showing only slowly progressive mental retardation and relatively mild skeletal abnormalities.