TY - JOUR
T1 - Aspartylglycosamine is a biomarker for NGLY1-CDDG, a congenital disorder of deglycosylation
AU - Haijes, Hanneke A.
AU - de Sain-van der Velden, Monique G.M.
AU - Prinsen, Hubertus C.M.T.
AU - Willems, Anke P.
AU - van der Ham, Maria
AU - Gerrits, Johan
AU - Couse, Madeline H.
AU - Friedman, Jan M.
AU - van Karnebeek, Clara D.M.
AU - Selby, Kathryn A.
AU - van Hasselt, Peter M.
AU - Verhoeven-Duif, Nanda M.
AU - Jans, Judith J.M.
N1 - Funding Information:
This work was supported by the personal Alexandre Suerman Stipend of the University Medical Centre Utrecht (H.A.H.) and by Metakids (2017–075) (J.J.M.J.). The studies performed on P4 were supported by the Canadian Institutes of Health Research ( CIHR – SCA-145104 ) through CHILD-BRIGHT (Child Health Initiative Limiting Disability – Brain Research Improving Growth and Health Trajectories), with additional support provided by BC Children's Hospital Foundation and the Michael Smith Foundation for Health Research .
Funding Information:
This work was supported by the personal Alexandre Suerman Stipend of the University Medical Centre Utrecht (H.A.H.) and by Metakids (2017–075) (J.J.M.J.). The studies performed on P4 were supported by the Canadian Institutes of Health Research (CIHR – SCA-145104) through CHILD-BRIGHT (Child Health Initiative Limiting Disability – Brain Research Improving Growth and Health Trajectories), with additional support provided by BC Children's Hospital Foundation and the Michael Smith Foundation for Health Research. We would like to thank the patients and their families for participation in this study.
Publisher Copyright:
© 2019 Elsevier Inc.
PY - 2019/8/1
Y1 - 2019/8/1
N2 - 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.
AB - 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.
KW - Aspartylglycosamine
KW - Biomarker
KW - NGLY1-CDDG
KW - Peptide:N-glycanase
UR - http://www.scopus.com/inward/record.url?scp=85068864523&partnerID=8YFLogxK
U2 - 10.1016/j.ymgme.2019.07.001
DO - 10.1016/j.ymgme.2019.07.001
M3 - Article
C2 - 31311714
SN - 1096-7192
VL - 127
SP - 368
EP - 372
JO - Molecular Genetics and Metabolism
JF - Molecular Genetics and Metabolism
IS - 4
ER -