bims-meglyc Biomed News
on Metabolic disorders affecting glycosylation
Issue of 2026–08–23
two papers selected by
Silvia Radenkovic, UMC Utrecht
  1. Integrated glycoproteomics reveals site-specific N-glycosylation defects in phosphomannomutase 2 congenital disorder of glycosylation.
  2. Stress-induced secretory pathway disruption causes atypical metalloproteinase transport in PMM2-CDG.
  1. J Biol Chem. 2026 Aug 19. pii: S0021-9258(26)02341-0. [Epub ahead of print] 113469
    Integrated glycoproteomics reveals site-specific N-glycosylation defects in phosphomannomutase 2 congenital disorder of glycosylation.
    Jonas Nilsson, Ekaterina Mirgorodskaya, Carina Sihlbom Wallem, Fredrik Noborn, Erik A Eklund, Göran Larson, Maria Blomqvist.
      The routine diagnostic pathway for congenital disorders of glycosylation (CDG) relies on the analysis of carbohydrate-deficient transferrin in serum, a test that incompletely captures defects in N-linked glycosylation and may also yield false-negative results even in classical N-glycosylation disorders such as PMM2-CDG. To explore molecular features of PMM2-CDG pathogenesis and identify potential biomarker candidates, we applied an integrated semiquantitative LC-MS/MS glycoproteomic workflow to a well-characterised cohort of individuals with PMM2-CDG (n = 7), alongside controls (n=9). The workflow combines the analysis of N-glycopeptides and corresponding non-glycosylated peptides in serum and plasma. Distinct disease-associated glycosylation patterns were observed in PMM2-CDG patients. Elevated levels of immature (paucimannose-like) N-glycans were detected at specific sites, including GlcNAc(2)Man(4) at Asn-85 of complement component 3, GlcNAc(2)Man(3) at Asn-869 of α-2-macroglobulin, and GlcNAc(2)Man(5) at Asn-226 of complement component 4. In parallel, approximately 50 peptides with unoccupied N-glycosylation sequons, including peptides from transferrin, were recurrently identified in CDG patient samples, indicating widespread reductions in N-glycosylation site occupancy. Together, this small cohort-based glycoproteomic analysis reveals coherent, site-specific disruptions in protein glycosylation that reflect underlying defects in mannose metabolism in PMM2-CDG. These molecular features define candidate glycophenotypes with potential utility as biomarkers for CDG subtype discrimination, disease stratification, and assessment of disease severity in future studies.
    Keywords:  N‐linked glycosylation; PMM2-CDG; biomarker; carbohydrate metabolism; congenital disorders of glycosylation (CDG); glycomics; glycopeptide; glycoproteomics; inborn error of metabolism; mass spectrometry (MS); spectral counting
    DOI:  https://doi.org/10.1016/j.jbc.2026.113469
  2. iScience. 2026 Aug 21. 29(8): 117152
    Stress-induced secretory pathway disruption causes atypical metalloproteinase transport in PMM2-CDG.
    Chia-Lun Wu, Kali Wiggins, Lynn Dukes-Rimsky, Kishore Garapati, Akhilesh Pandey, Richard Steet, Heather Flanagan-Steet.
      Matrix metalloproteinase (Mmp) dysfunction has been implicated as a driver of cartilage and neuromuscular pathologies in a common congenital disorder of glycosylation, PMM2-CDG. Since Mmp activity and interactions can be regulated by their glycans, these abnormalities were thought to likely arise from direct effects on enzyme glycosylation. However, here we show that disruptions in secretory pathway morphology alter the trafficking of Mmp2 and its activator, membrane-type Mmp MT1-Mmp. Biochemical and visual studies indicate enhanced processing by a furin proconvertase causes MT1-Mmp to directly exit the ER, bypassing the Golgi. This unconventional route of cell surface transport prevents MT1-Mmp and Mmp2 from interacting inside chondrocytes, causing pro-Mmp2 to accumulate in the Golgi. Importantly, defects in Mmp trafficking do not appear to correspond to direct defects in the N-glycosylation of either enzyme, suggesting that stress-induced alterations in secretory pathway organization may instead underlie the atypical Mmp trafficking in PMM2-CDG.
    Keywords:  CDG; MMP; glycosylation; secretory pathway; unconventional trafficking
    DOI:  https://doi.org/10.1016/j.isci.2026.117152
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