Aspartylglycosamine is a biomarker for NGLY1-CDDG, a congenital disorder of deglycosylation.

Abstract

BACKGROUND:

NGLY1-CDDG is a congenital disorder of deglycosylation caused by a defective peptide:N-glycanase (PNG). To date, all but one of the reported patients have been diagnosed through whole-exome or whole-genome sequencing, as no biochemical marker was available to identify this disease in patients. Recently, a potential urinary biomarker was reported, but the data presented suggest that this marker may be excreted intermittently.

METHODS:

In this study, we performed untargeted direct-infusion high-resolution mass spectrometry metabolomics in seven dried blood spots (DBS) from four recently diagnosed NGLY1-CDDG patients, to test for small-molecule biomarkers, in order to identify a potential diagnostic marker. Results were compared to 125 DBS of healthy controls and to 238 DBS of patients with other diseases.

RESULTS:

We identified aspartylglycosamine as the only significantly increased compound with a median Z-score of 4.8 (range: 3.8-8.5) in DBS of NGLY1-CDDG patients, compared to a median Z-score of -0.1 (range: -2.1-4.0) in DBS of healthy controls and patients with other diseases.

DISCUSSION:

The increase of aspartylglycosamine can be explained by lack of function of PNG. PNG catalyzes the cleavage of the proximal N-acetylglucosamine residue of an N-glycan from the asparagine residue of a protein, a step in the degradation of misfolded glycoproteins. PNG deficiency results in a single N-acetylglucosamine residue left attached to the asparagine residue which results in free aspartylglycosamine when the glycoprotein is degraded. Thus, we here identified aspartylglycosamine as the first potential small-molecule biomarker in DBS for NGLY1-CDDG, making a biochemical diagnosis for NGLY1-CDDG potentially feasible.

• Authors: Hanneke A Haijes, Monique G M de Sain-van der Velden, Hubertus C M T Prinsen, Anke P Willems, Maria van der Ham, Johan Gerrits, Madeline H Couse, Jan M Friedman, Clara D M van Karnebeek, Kathryn A Selby, Peter M van Hasselt, Nanda M Verhoeven-Duif, Judith J M Jans
• Journal: Molecular genetics and metabolism (Mol Genet Metab) Vol. 127 Issue 4 Pg. 368-372 (08 2019) ISSN: 1096-7206 [Electronic] United States
• PMID: 31311714 (Publication Type: Case Reports, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 Elsevier Inc. All rights reserved.

Chemical References

• Biomarkers
• N-acetylglucosaminylasparagine
• Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase
• Acetylglucosamine

Topics

• Acetylglucosamine (analogs & derivatives, blood)
• Adolescent
• Adult
• Biomarkers (blood)
• Case-Control Studies
• Child
• Child, Preschool
• Congenital Disorders of Glycosylation (blood, diagnosis)
• Dried Blood Spot Testing
• Female
• Humans
• Infant
• Male
• Mass Spectrometry
• Mutation
• Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase (blood, deficiency)