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Glycobiology Advance Access originally published online on September 1, 2004
Glycobiology 2005 15(1):79-85; doi:10.1093/glycob/cwh145
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Glycobiology vol. 15 no. 1 © Oxford University Press 2005; all rights reserved.

Massive accumulation of Man2GlcNAc2-Asn in nonneuronal tissues of glycosylasparaginase-deficient mice and its removal by enzyme replacement therapy

Eira Kelo2, Ulla Dunder2 and Ilkka Mononen1,3

2 Laboratory Centre, Kuopio University Hospital, FIN-70210 Kuopio, Finland and 3 Department of Clinical Chemistry, University of Turku and TUCH Laboratories, PO Box 52, FIN-20521 Turku, Finland

1 To whom correspondence should be addressed; e-mail: ilkka.mononen{at}tyks.fi

Received on June 21, 2004; revised on August 27, 2004; accepted on August 30, 2004

Aspartylglycosaminuria (AGU) is caused by deficient enzymatic activity of glycosylasparaginase (GA). The disease is characterized by accumulation of aspartylglucosamine (GlcNAc-Asn) and other glycoasparagines in tissues and body fluids of AGU patients and in an AGU mouse model. In the current study, we characterized a glycoasparagine carrying the tetrasaccharide moiety of {alpha}-D-Man-(1->6)-ß-D-Man-(1->4)-ß-D-GlcNAc-(1->4)-ß-D-GlcNAc-(1->N)-Asn (Man2GlcNAc2-Asn) in urine of an AGU patient and also in the tissues of the AGU mouse model. Quantitative analysis demonstrated a massive accumulation of the compound especially in nonneuronal tissues of the AGU mice, in which the levels of Man2GlcNAc2-Asn were typically 30–87% of those of GlcNAc-Asn. The highest level of Man2GlcNAc2-Asn was found in the liver, spleen, and heart tissues of the AGU mice, the respective amounts being 87%, 76%, and 57% of the GlcNAc-Asn levels. In the brain tissue of AGU mice the Man2GlcNAc2-Asn storage was only 9% of that of GlcNAc-Asn. In contrast to GlcNAc-Asn, the storage of Man2GlcNAc2-Asn markedly increased in the liver and spleen tissues of AGU mice as they grew older. Enzyme replacement therapy with glycosylasparaginase for 3.5 weeks reduced the amount of Man2GlcNAc2-Asn by 66–97% in nonneuronal tissues, but only by 13% in the brain tissue of the AGU mice. In conclusion, there is evidence for a role for storage of glycoasparagines other than aspartylglucosamine in the pathogenesis of AGU, and this possibility should be taken into consideration in the treatment of the disease.

Key words: aspartylglucosaminuria / enzyme replacement / lysosomal enzymes / lysosomal storage / N-linked oligosaccharide


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