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© 2024. This work is published under https://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.

Abstract

BACKGROUND. Diagnosis of PMM2-CDG, the most common congenital disorder of glycosylation (CDG), relies on measuring carbohydrate-deficient transferrin (CDT) and genetic testing. CDT tests have false negatives and may normalize with age. Site-specific changes in protein N-glycosylation have not been reported in sera in PMM2-CDG.

METHODS. Using multistep mass spectrometry–based N-glycoproteomics, we analyzed sera from 72 individuals to discover and validate glycopeptide alterations. We performed comprehensive tandem mass tag–based discovery experiments in well-characterized patients and controls. Next, we developed a method for rapid profiling of additional samples. Finally, targeted mass spectrometry was used for validation in an independent set of samples in a blinded fashion.

RESULTS. Of the 3,342 N-glycopeptides identified, patients exhibited decrease in complex-type N-glycans and increase in truncated, mannose-rich, and hybrid species. We identified a glycopeptide from complement C4 carrying the glycan Man5GlcNAc2, which was not detected in controls, in 5 patients with normal CDT results, including 1 after liver transplant and 2 with a known genetic variant associated with mild disease, indicating greater sensitivity than CDT. It was detected by targeted analysis in 2 individuals with variants of uncertain significance in PMM2.

CONCLUSION. Complement C4–derived Man5GlcNAc2 glycopeptide could be a biomarker for accurate diagnosis and therapeutic monitoring of patients with PMM2-CDG and other CDGs.

FUNDING. U54NS115198 (Frontiers in Congenital Disorders of Glycosylation: NINDS; NCATS; Eunice Kennedy Shriver NICHD; Rare Disorders Consortium Disease Network); K08NS118119 (NINDS); Minnesota Partnership for Biotechnology and Medical Genomics; Rocket Fund; R01DK099551 (NIDDK); Mayo Clinic DERIVE Office; Mayo Clinic Center for Biomedical Discovery; IA/CRC/20/1/600002 (Center for Rare Disease Diagnosis, Research and Training; DBT/Wellcome Trust India Alliance)

Details

Title
A complement C4–derived glycopeptide is a biomarker for PMM2-CDG
Author
Garapati, Kishore; Budhraja, Rohit; Saraswat, Mayank; Kim, Jinyong; Joshi, Neha; Sachdeva, Gunveen S; Jain, Anu; Ligezka, Anna N; Radenkovic, Silvia; Ramarajan, Madan Gopal; Udainiya, Savita; Kimiyo Raymond; He, Miao; Lam, Christina; Larson, Austin; Edmondson, Andrew C; Sarafoglou, Kyriakie; Larson, Nicholas B; Freeze, Hudson H; Schultz, Matthew J; Kozicz, Tamas; Morava, Eva; Pandey, Akhilesh
Section
Research Articles
Publication year
2024
Publication date
Apr 2024
Publisher
American Society for Clinical Investigation
e-ISSN
23793708
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
3256004752
Copyright
© 2024. This work is published under https://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.