Aspartylglucosaminuria (AGU, McKusick 208400) is an autosomal recessive
lysosomal storage disease caused by defective degradation of Asn-linked
glycoproteins. AGU mutations occur in the gene (AGA) for
glycosylasparaginase, the
enzyme necessary for hydrolysis of the
protein oligosaccharide linkage in Asn-linked
glycoprotein substrates undergoing metabolic turnover. Loss of
glycosylasparaginase activity leads to accumulation of the linkage unit Asn-GlcNAc in tissue lysosomes. Storage of this fragment affects the pathophysiology of neuronal cells most severely. The patients notably suffer from decreased cognitive abilities, skeletal abnormalities and facial grotesqueness. The progress of the disease is slower than in many other
lysosomal storage diseases. The patients appear normal during infancy and generally live from 25 to 45 years. A specific AGU mutation is concentrated in the Finnish population with over 200 patients. The carrier frequency in Finland has been estimated to be in the range of 2.5-3% of the population. So far there are 20 other rare family AGU alleles that have been characterized at the molecular level in the world's population. Recently, two knockout mouse models for AGU have been developed. In addition, the crystal structure of human leukocyte
glycosylasparaginase has been determined and the
protein has a unique alphabetabetaalpha sandwich fold shared by a newly recognized family of important
enzymes called N-terminal nucleophile (Ntn)
hydrolases. The nascent single-chain precursor of glycosylase araginase self-cleaves into its mature alpha- and beta-subunits, a reaction required to activate the
enzyme. This interesting biochemical feature is also shared by most of the
Ntn-hydrolase family of
proteins. Many of the disease-causing mutations prevent proper folding and subsequent activation of the
glycosylasparaginase.