Mice with an aspartylglucosaminuria mutation similar to humans replicate the pathophysiology in patients

Aspartyglucosaminuria (AGU) is a lysosomal storage disease with autosomalrecessive inheritance that is caused by deficient activity ofaspartylglucosaminidase (AGA), a lysosomal enzyme belonging to the newlydescribed enzyme family of N-terminal hydrolases. An AGU mouse model wasgenerated by targeted disruption of the AGA gene designed to mimic closelyone human disease mutation. These homozygous mutant mice have no detectableAGA activity and excrete aspartylglucosamine in their urine. Analogously tothe human disease, the affected homozygous animals showed storage inlysosomes in all analyzed tissues, including the brain, liver, kidney andskin, and lysosomal storage was already detected in fetuses at 19 daysgestation. Electron microscopic studies of brain tissue samplesdemonstrated lysosomal storage vacuoles in the neurons and glia of theneocortical and cortical regions. Magnetic resonance images (MRI)facilitating monitoring of the brains of living animals indicated cerebralatrophy and hypointensity of the deep gray matter structures ofbrain-findings similar to those observed in human patients. AGU mice arefertile, and up to 11 months of age their movement and behavior do notdiffer from their age-matched littermates. However, in the Morris watermaze test, a slow worsening of performance could be seen with age. Thephenotype mimics well AGU in humans, the patients characteristicallyshowing only slowly progressive mental retardation and relatively mildskeletal abnormalities.