A complement C4–derived glycopeptide is a biomarker for PMM2-CDG
Year: 2024
Type: article
Study design: Observational Study
Abstract: BACKGROUNDDiagnosis 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.METHODSUsing 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.RESULTSOf 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.CONCLUSIONComplement C4-derived Man5GlcNAc2 glycopeptide could be a biomarker for accurate diagnosis and therapeutic monitoring of patients with PMM2-CDG and other CDGs.FUNDINGU54NS115198 (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).
Source: JCI Insight
Authors: Kishore Garapati, Rohit Budhraja, Mayank Saraswat, Jinyong Kim, Neha Joshi, Gunveen S. Sachdeva, Anu Jain, Anna N. Ligezka, Silvia Radenkovic, Madan Gopal Ramarajan, Savita Udainiya, Kimiyo Raymond, Miao He, Christina Lam, Austin Larson, Andrew C. Edmondson, Kyriakie Sarafoglou, Nicholas B. Larson, Hudson H. Freeze, Matthew J. Schultz, Tamas Kozicz, Eva Morava, Akhilesh Pandey
Institutions: Mayo Clinic, Manipal Academy of Higher Education, Institute of Bioinformatics, Children's Hospital of Philadelphia, University of Washington, Seattle Children's Research Institute, University of Minnesota, Sanford Burnham Prebys Medical Discovery Institute, Mount Sinai Hospital, University of Pecs, Icahn School of Medicine at Mount Sinai
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $4,100
Funders: Children's Hospital of Philadelphia, University of Minnesota, Wellcome Trust, Department of Biotechnology, Ministry of Science and Technology, India, Astellas Pharma, The Wellcome Trust DBT India Alliance, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Neurological Disorders and Stroke, National Institute of Child Health and Human Development, National Center for Advancing Translational Sciences, Eunice Kennedy Shriver National Institute of Child Health and Human Development
OpenAlex ID: W4394063990