bims-meglyc Biomed News
on Metabolic disorders affecting glycosylation
Issue of 2025–07–20
four papers selected by
Silvia Radenkovic, UMC Utrecht



  1. bioRxiv. 2025 Jul 10. pii: 2025.07.07.663468. [Epub ahead of print]
       Background: Congenital Disorders of Glycosylation (CDG) are a rapidly expanding group of inherited metabolic diseases caused by defects in glycosylation. Although over 190 genetic defects have been identified, effective treatments remain available for only a few. We hypothesized that integrative analysis of multi-omics datasets from individuals with various CDG could uncover common molecular signatures and highlight shared therapeutic targets.
    Methods: We compiled all publicly available RNA sequencing, proteomics and glycoproteomics datasets from patients with PMM2-CDG, ALG1-CDG, SRD5A3-CDG, NGLY1-CDDG, ALG13-CDG and PGM1-CDG, spanning different tissues, including induced cardiomyocytes, human cortical organoids, fibroblasts, and lymphoblasts. Differential expression and glycosylation analyses were performed, followed by Gene Set Enrichment Analysis (GSEA) to identify commonly dysregulated pathways. We then applied the EMUDRA drug prediction algorithm to prioritize candidate compounds capable of reversing these shared molecular signatures.
    Results: We identified four glycoproteins with consistent differential glycosylation across all eight glycoproteomics datasets. Six glycosylation sites and glycan structures were recurrently altered across CDG and showed partial correction with treatment. Pathway analysis revealed shared disruptions in autophagy, vesicle trafficking, and mitochondrial function. EMUDRA predicted several repurposable drug classes, including muscle relaxants, antioxidants, beta-adrenergic agonists, antibiotics, and NSAIDs, that could reverse key pathway abnormalities, particularly those involving autophagy and N-glycosylation.
    Conclusion: Most dysregulated pathways were shared across CDG, suggesting the potential for common therapeutic strategies. Several candidate drugs targeting these shared abnormalities emerged from integrative analysis and warrant validation in future in vitro studies.
    DOI:  https://doi.org/10.1101/2025.07.07.663468
  2. Res Sq. 2025 Jul 10. pii: rs.3.rs-6882753. [Epub ahead of print]
      The lack of a molecular understanding of mood disorders has impeded progress in diagnosis and treatment. Glycosylation may provide insights into the complex mechanisms underlying these conditions. We conducted N-glycoproteomic analysis on dorsolateral prefrontal cortex samples from individuals with major depressive disorder (MDD) and bipolar disorder (BD), in depressive or manic states at death. Additionally, we examined depression prevalence in congenital disorders of glycosylation (CDG) through a literature review and assessment of 110 CDG patients. Glycoproteomic analysis revealed a significant increase in protein glycosylation in individuals with MDD relative to both controls and individuals with BD. Depression prevalence was lower in our pediatric and adult cohort of individuals with CDG. These results suggest brain glycosylation changes may play a role in mood disorder pathology and highlight the distinct biology of unipolar and bipolar depression. Our findings propose that impaired glycosylation may confer resilience to depression, offering potential therapeutic insights.
    DOI:  https://doi.org/10.21203/rs.3.rs-6882753/v1
  3. Biochem Biophys Res Commun. 2025 Jul 11. pii: S0006-291X(25)01046-0. [Epub ahead of print]778 152331
      Mannosyl-oligosaccharide Glucosidase (MOGS) initiates glycan trimming by specifically cleaving α-1,2-linked glucose residues on glycoproteins. MOGS is a key enzyme for proper N-glycosylation, and its defects are associated with rare disease MOGS related congenital disorders of glycosylation (MOGS-CDG). Although MOGS has been identified from most of eukaryotic organisms, its existence in prokaryotic remains unclear. In this study, a prokaryotic MOGS (pMOGS) was identified from Elizabethkingia meningoseptica FMS-007. During the process, a functional complementation assay was established by examining the N-glycans profile of a CWH41 (MOGS homologous gene) knockout strain of Saccharomyces cerevisiae. Using the assay system, the function of human MOGS and its disease related mutants were tested. This study extended our understandings of MOGS and our ability to approach MOGS-CDG.
    Keywords:  CWH41; Congenital disorders of glycosylation (CDG); Functional complementation; Mannosyl-oligosaccharide Glucosidase (MOGS); Prokaryotic MOGS (pMOGS); Rare disease
    DOI:  https://doi.org/10.1016/j.bbrc.2025.152331
  4. J Neuromuscul Dis. 2025 Jul 15. 22143602251360270
      BackgroundB3GALNT2 mutations cause α-dystroglycanopathy (α-DGP), a rare condition characterized by muscular dystrophy, brain malformations, and developmental delay. However, its pathogenic mechanisms remain poorly understood. To date, limited cases have been reported, and the pathogenic mechanisms remain incompletely understood.MethodsClinical and genetic data from 3 newly diagnosed Chinese patients and 28 patients previously diagnosed with B3GALNT2-related α-DGP were analyzed. Using patient-derived fibroblasts, α-dystroglycan (α-DG) glycosylation and laminin-binding capacity were assessed by immunoblotting, laminin overlay and immunofluorescence. B3GALNT2 mRNA and protein levels were quantified by real-time PCR and immunoblotting. Enzymatic activity was measured using purified recombinant B3GALNT2 proteins. Differentially expressed genes were identified via an mRNA microarray.ResultsAll three patients carried compound heterozygous variants involving one truncating and one missense mutation. Two novel mutations (c.657_658insTT and c.1384T > C) were identified. Functional studies confirmed that the missense mutations (Y436C and C462R) impaired enzymatic activity to 40-50% of wild-type levels, while splice variants caused frameshifts and likely complete loss of protein. Despite partial residual activity, all patients showed severely reduced α-DG glycosylation and loss of laminin binding, consistent with a functional threshold effect. Transcriptomic analysis revealed upregulation of CHST10 in two patients.ConclusionsThis study expands the mutational spectrum of B3GALNT2-related α-DGP and provides mechanistic insight into the pathogenicity of novel variants. Our findings support a functional threshold model for B3GALNT2 activity in α-DG glycosylation and suggest CHST10 as a potential transcriptional responder to glycosylation defects. These results deepen the understanding of B3GALNT2-related dystroglycanopathies and may inform future diagnostic and therapeutic strategies.
    Keywords:  B3GALNT2; CHST10; enzyme activity; glycosyltransferase; sulfation; α-dystroglycanopathies
    DOI:  https://doi.org/10.1177/22143602251360270