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Gene Review

Aga  -  aspartylglucosaminidase

Mus musculus

Synonyms: AGA, AW060726, Aspartylglucosaminidase, Glycosylasparaginase, N(4)-(beta-N-acetylglucosaminyl)-L-asparaginase, ...
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Disease relevance of Aga

  • Aspartyglucosaminuria (AGU) is a lysosomal storage disease with autosomal recessive inheritance that is caused by deficient activity of aspartylglucosaminidase (AGA), a lysosomal enzyme belonging to the newly described enzyme family of N-terminal hydrolases [1].
  • In general, E. coli asparaginase treatment had much less effect on these measurements than did AGA [2].
  • By Day 8, either the zero protein diet or AGA treatment significantly reduced ascites volume and tumor nitrogen content relative to controls [3].
  • The effects of Acinetobacter glutaminase-asparaginase (AGA) on protein and energy requirements were evaluated in mice bearing Ehrlich ascites tumors [3].
  • These experiments indicate that the requirements and utilization of energy and nitrogen are normal in mice with Ehrlich ascites tumor whether or not they are treated with AGA [3].

High impact information on Aga

  • Aspartylglycosaminuria (AGU), the most common disorder of glycoprotein degradation in humans, is caused by mutations in the gene encoding the lysosomal enzyme glycosylasparaginase (Aga) [4].
  • Through targeted disruption of the mouse Aga gene in embryonic stem cells, we generated mice that completely lack Aga activity [4].
  • These homozygous mutant mice have no detectable AGA activity and excrete aspartylglucosamine in their urine [1].
  • Endocytotic capability of cultured telencephalic neurons was comparable to that of fibroblasts, and endocytosis of AGA was blocked by free mannose-6-phosphate (M6P), indicating that uptake of the enzyme was mediated by M6P receptors (M6PRs) [5].
  • Neither tumor nor AGA treatment affected body composition or the efficiency of nitrogen utilization [3].

Chemical compound and disease context of Aga


Biological context of Aga

  • The mouse Aga gene was localized to the central area of the B region of chromosome 8, which represents the synteny group in the human chromosome 4q telomeric region where the human AGA gene is located [7].
  • We isolated and characterized human and mouse AGA 5'-flanking sequences including the promoter regions [8].
  • In this study, we have used our recently developed mouse model for AGU and analyzed processing, intracellular localization, and endocytosis of recombinant AGA in telencephalic AGU mouse neurons in vitro [5].
  • In addition, the X. laevis mitochondrial genome employs the encoded AGA stop codon once and the UAA stop codon three times and requires polyadenylation to provide the nine other UAA stop codons [9].
  • The consensus DNA sequence for each repeat is CCA CCA CCA CCA GGA GGC CCA CAG CCG AGA CCC CCT CAA GGC [10].

Anatomical context of Aga

  • Expression of the mouse Aga cDNA in COS-1 cells showed that the mouse Aga polypeptide was processed similarly to the human counterpart [7].
  • These findings demonstrate that the glycosylasparaginase-deficient mice share many neuropathological features with human AGU patients, providing a suitable animal model to test therapeutic strategies in the treatment of the central nervous system effects in AGU [11].
  • AGA treatment produced partial depletion of glutamine concentrations in muscle, spleen, small intestine, and liver [2].
  • Two major T cell determinants are recognized by I-Ar-specific T cells in CII, the immunodominant CII610-618 (GPAGT AGA R) within CB10 and the subdominant CII445-453 (GPAGP AGE R) within CB8 [12].
  • CONCLUSIONS: These data indicate the importance of glial cells in the expression and transport of AGA [13].

Associations of Aga with chemical compounds

  • Despite over 100-fold increase in plasma glutamate, only the kidney showed a substantial increase in free glutamate levels during AGA treatment [2].
  • However, the AGA codons found in these four polypeptide genes correspond in position to codons which specify nine different amino acids, but never arginine, in the equivalent polypeptide gene which have been sequenced from mtDNAs of mouse, yeast and Zea mays [14].

Analytical, diagnostic and therapeutic context of Aga


  1. Mice with an aspartylglucosaminuria mutation similar to humans replicate the pathophysiology in patients. Jalanko, A., Tenhunen, K., McKinney, C.E., LaMarca, M.E., Rapola, J., Autti, T., Joensuu, R., Manninen, T., Sipilä, I., Ikonen, S., Riekkinen, P., Ginns, E.I., Peltonen, L. Hum. Mol. Genet. (1998) [Pubmed]
  2. Effect of Acinetobacter glutaminase-asparaginase treatment on free amino acids in mouse tissues. Holcenberg, J.S., Tang, E., Dolowy, W.C. Cancer Res. (1975) [Pubmed]
  3. Nitrogen utilization in mice bearing Ehrlich ascites tumor treated with Acinetobacter glutaminase-asparaginase. Kien, C.L., Holcenberg, J.S. Cancer Res. (1981) [Pubmed]
  4. A mouse model for the human lysosomal disease aspartylglycosaminuria. Kaartinen, V., Mononen, I., Voncken, J.W., Noronkoski, T., Gonzalez-Gomez, I., Heisterkamp, N., Groffen, J. Nat. Med. (1996) [Pubmed]
  5. Expression and endocytosis of lysosomal aspartylglucosaminidase in mouse primary neurons. Kyttälä, A., Heinonen, O., Peltonen, L., Jalanko, A. J. Neurosci. (1998) [Pubmed]
  6. Dosage effect of minor arginyl- and isoleucyl-tRNAs on protein synthesis in an Escherichia coli in vitro coupled transcription/translation system. Jiang, X., Nakano, H., Kigawa, T., Yabuki, T., Yokoyama, S., Clark, D.S., Yamane, T. J. Biosci. Bioeng. (2001) [Pubmed]
  7. Molecular cloning, chromosomal assignment, and expression of the mouse aspartylglucosaminidase gene. Tenhunen, K., Laan, M., Manninen, T., Palotie, A., Peltonen, L., Jalanko, A. Genomics (1995) [Pubmed]
  8. Expression and regulation of the human and mouse aspartylglucosaminidase gene. Uusitalo, A., Tenhunen, K., Tenhunen, J., Matikainen, S., Peltonen, L., Jalanko, A. J. Biol. Chem. (1997) [Pubmed]
  9. The complete nucleotide sequence of the Xenopus laevis mitochondrial genome. Roe, B.A., Ma, D.P., Wilson, R.K., Wong, J.F. J. Biol. Chem. (1985) [Pubmed]
  10. The structure and organization of a proline-rich protein gene of a mouse multigene family. Ann, D.K., Carlson, D.M. J. Biol. Chem. (1985) [Pubmed]
  11. Progressive neurodegeneration in aspartylglycosaminuria mice. Gonzalez-Gomez, I., Mononen, I., Heisterkamp, N., Groffen, J., Kaartinen, V. Am. J. Pathol. (1998) [Pubmed]
  12. Immunogenicity and arthritogenicity of recombinant CB10 in B10.RIII mice. Tang, B., Brand, D.D., Chiang, T.M., Stuart, J.M., Kang, A.H., Myers, L.K. J. Immunol. (2000) [Pubmed]
  13. Aspartylglucosaminidase (AGA) is efficiently produced and endocytosed by glial cells: implication for the therapy of a lysosomal storage disorder. Harkke, S., Laine, M., Jalanko, A. The journal of gene medicine. (2003) [Pubmed]
  14. Nucleotide sequence of a segment of Drosophila mitochondrial DNA that contains the genes for cytochrome c oxidase subunits II and III and ATPase subunit 6. Clary, D.O., Wolstenholme, D.R. Nucleic Acids Res. (1983) [Pubmed]
  15. Correction of peripheral lysosomal accumulation in mice with aspartylglucosaminuria by bone marrow transplantation. Laine, M., Richter, J., Fahlman, C., Rapola, J., Renlund, M., Peltonen, L., Karlsson, S., Jalanko, A. Exp. Hematol. (1999) [Pubmed]
  16. Further improvement of dye-exclusion microcytotoxicity assay by introducing low melting point agarose into the medium. Kubota, E., Ishikawa, H., Saito, K. J. Immunol. Methods (1983) [Pubmed]
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