Aspartylglycosaminuria: biochemistry and molecular biology

Abstract

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.

Genome-Wide Association Study of Serum Selenium Concentrations

“…rs1395479 is located in an intergenic region between the aspartylglucosaminidase ( AGA ) gene (~33 kb downstream) and the NEIL3 gene (~35 kb downstream). AGA is involved in the lysosomal breakdown of glycoproteins [42]. Glycoproteins occur in the cytosol, cell membrane, and extracellular space [43].…”

Oligosaccharide Analysis in Urine by MALDI-TOF Mass Spectrometry for the Diagnosis of Lysosomal Storage Diseases

“…A genetic deficiency of aspartylglucosaminidase causes the accumulation of glycoaminoacids, e.g., GlcNAc-Asn and other glycoproteins in lysosomes, leading to AGU (11,12 ). The representative urinary FOS spectra from the patients (n ϭ 4) with AGU revealed major diagnostic permethylated glycoamino acids at m/z 629.1, 990.28, 1078.01, and 1439.43, with the predicted composition and structure shown in Table 1.…”

Structural Basis of a Point Mutation that Causes the Genetic Disease Aspartylglucosaminuria

“…Due to a founder effect, AGU is enriched in Finland. However, the majority of AGU alleles are found outside Finland with sporadic AGU causing mutations (Aronson, 1999; Hreidarsson et al, 1983; Ikonen et al, 1991; Opladen et al, 2014). …”

“…AGU mutations occur in the gene of a well-known lysosomal enzyme glycosylasparaginase (GA), which is also known as aspartylglucosaminidase (Aronson, 1999; Mononen et al, 1993). GA is an amidase that cleaves the Asn-linked glycoprotein.…”

“…Molecular characterizations of AGU causing mutations revealed problems in autoproteolytic processing of their precursors. Thus AGU molecules are misprocessed and are retained at the pre-autoproteolysis stage as single-chain precursors, inactive for glycoprotein processing (Aronson, 1999; Saarela et al, 2001). …”