2. Academic Validation
  3. Aspartylglycosamine is a biomarker for NGLY1-CDDG, a congenital disorder of deglycosylation

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

  • Mol Genet Metab. 2019 Aug;127(4):368-372. doi: 10.1016/j.ymgme.2019.07.001.
Hanneke A Haijes 1,  Monique G M de Sain-van der Velden 2,  Hubertus C M T Prinsen 2,  Anke P Willems 2,  Maria van der Ham 2,  Johan Gerrits 2,  Madeline H Couse 3,  Jan M Friedman 3,  Clara D M van Karnebeek 4,  Kathryn A Selby 5,  Peter M van Hasselt 6,  Nanda M Verhoeven-Duif 2,  Judith J M Jans 7
Affiliations

Affiliations

  • 1 Section Metabolic Diagnostics, Department of Genetics, Utrecht University, University Medical Centre Utrecht, Lundlaan 6, 3584 EA Utrecht, the Netherlands; Section Metabolic Diseases, Department of Child Health, Wilhelmina Children's Hospital, University Medical Centre Utrecht, Utrecht University, Lundlaan 6, 3584 EA Utrecht, the Netherlands. Electronic address: h.a.siepel-3@umcutrecht.nl.
  • 2 Section Metabolic Diagnostics, Department of Genetics, Utrecht University, University Medical Centre Utrecht, Lundlaan 6, 3584 EA Utrecht, the Netherlands.
  • 3 Medical Genetics Research Unit,Children's and Women's Hospital, University of British Columbia Department of Medical Genetics, 4500 Oak Street, Vancouver, BC V6H 3N1, Canada.
  • 4 Departments of Pediatrics and Clinical Genetics, Emma Children's Hospital, University of Amsterdam, Amsterdam University Medical Centers, Meibergdreef 9, 1105 AZ, Amsterdam, the Netherlands; Department of Pediatrics, Children's and Women's Hospital, University of British Columbia, 4500 Oak Street, Vancouver, BC V6H 3N1, Canada; Centre for Molecular Medicine and Therapeutics, BC Children's Research Institute, University of British Columbia, 4500 Oak Street, Vancouver, BC V6H 3N1, Canada.
  • 5 Department of Pediatrics, Children's and Women's Hospital, University of British Columbia, 4500 Oak Street, Vancouver, BC V6H 3N1, Canada.
  • 6 Section Metabolic Diseases, Department of Child Health, Wilhelmina Children's Hospital, University Medical Centre Utrecht, Utrecht University, Lundlaan 6, 3584 EA Utrecht, the Netherlands.
  • 7 Section Metabolic Diagnostics, Department of Genetics, Utrecht University, University Medical Centre Utrecht, Lundlaan 6, 3584 EA Utrecht, the Netherlands. Electronic address: J.J.M.Jans@umcutrecht.nl.
PMID: 31311714 DOI: 10.1016/j.ymgme.2019.07.001
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.

Keywords

Aspartylglycosamine; Biomarker; NGLY1-CDDG; Peptide:N-glycanase.

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