bims-meglyc Biomed News
on Metabolic disorders affecting glycosylation
Issue of 2025–11–02
six papers selected by
Silvia Radenkovic, UMC Utrecht
  1. Assessment of Lectin Staining Biomarkers using a Murine Model of GNE Myopathy.
  2. Atypical Phenotype of Predominant Autoimmune Cytopenia and Impaired Perforin Expression in XMEN Syndrome.
  3. Oral D-mannose therapy during pregnancy in a woman with MPI-CDG: A case report and management review.
  4. Human O-GlcNAc transferase substrate recognition via MALDI-TOF MS quantification of peptide glycosylation.
  5. Two case reports and a literature review of hyperphosphatasia with intellectual disability syndrome 2 caused by a PIGO mutation.
  6. Oligosaccharyltransferase Is Involved in Targeting to ER-Associated Degradation.
  1. MicroPubl Biol. 2025 ;2025
    Assessment of Lectin Staining Biomarkers using a Murine Model of GNE Myopathy.
    Olivia Parker, Jordyn Woods, Max Rothkopf, Daniel Drach, Hanna N Wetzel, Kelly E Crowe.
      GNE myopathy (GNEM) is a rare myopathy caused by mutations in the UDP-GlcNAc epimerase/ManNAc-6 kinase (GNE) gene, which reduce sialic acid (SA) biosynthesis and impair muscle through unclear mechanisms. As development of SA-restoring GNEM gene therapies is underway, it is essential to develop SA-detecting biomarkers in preclinically-relevant murine tissues. Here, we assess skeletal muscle staining of the Gne M743T/M743T GNEM model with four sialylation-detecting lectins. While no tested lectins could effectively differentiate between Gne M743T/M743T and wild type tissues, Peanut Agglutinin (PNA) showed differential binding in tissues with and without SA-removing sialidase treatment, indicating its promise in detecting hyposialylation in murine tissues.
    DOI:  https://doi.org/10.17912/micropub.biology.001717
  2. J Immunol Res. 2025 ;2025 3161910
    Atypical Phenotype of Predominant Autoimmune Cytopenia and Impaired Perforin Expression in XMEN Syndrome.
    Hana Grombirikova, Adam Markocsy, Anna Kocurkova, Jan Blatny, Marcela Vlkova, Peter Slanina, Eva Hlavackova, Veronika Fiamoli, Helena Schneiderova, Adam Klocperk, Dita Ricna, Eva Fronkova, Jan Kral, Anna Salingova, Milos Jesenak, Tomas Freiberger.
      X-linked immunodeficiency with magnesium defect, Epstein-Barr virus (EBV) infection, and neoplasia (XMEN) is caused by a pathogenic variant in the magnesium transporter 1 (MAGT1) gene. The defect leads to impaired N-glycosylation which affects various immune processes. In this study, we described the disease course, clinical features and laboratory parameters observed in six patients from three families diagnosed with XMEN syndrome. They exhibit heterogeneous clinical manifestation while displaying typical laboratory signs of the disease, including decreased surface expression of NKG2D and CD28 on CD8+ T-cells and NK cells, as well as defects in the N-glycosylation of transferrin. We identified two novel variants in the cohort: a frameshift variant c.444dup in exon 3, and a splicing variant c.998-20_1008del. Notably, a patient with the c.444dup variant presented with severe autoimmune cytopenia as an isolated manifestation of the disease, while his younger brother, carrying the same variant, exhibited predominantly mild skin infections. These findings illustrate varying degrees of severity in penetrance and highlight that some patients may exhibit only partial symptoms. Furthermore, our study confirmed defects in perforin expression in XMEN syndrome. We observed a significant reduction in perforin expression within CD8+ T-cells and NK cells which may lead to increased susceptibility to recurrent infections and autoimmune complications frequently observed in XMEN patients.
    Keywords:  MAGT1; XMEN; autoimmune cytopenia; autoimmune haemolytic anaemia; congenital disorders of glycosylation; immune thrombocytopenia; perforin
    DOI:  https://doi.org/10.1155/jimr/3161910
  3. Mol Genet Metab. 2025 Oct 28. pii: S1096-7192(25)00261-6. [Epub ahead of print]146(4): 109269
    Oral D-mannose therapy during pregnancy in a woman with MPI-CDG: A case report and management review.
    Lionel Martzolff, Alexandre Raynor, Elodie Lebredonchel, Sara Marescaux, Dominique Desprez, Claire Douillard, Laure Federici, Isabelle Alamome, Nathalie Trillot, Jean-Meidi Alili, Annie Harroche, Delphine Borgel, Camille Wicker, Jean-Edouard Terrade, Arnaud Bruneel, Pascale De Lonlay.
      Mannose 6-phosphate isomerase deficiency is a rare disorder of N-glycosylation leading to impaired coagulation, enteropathy, hypoglycemia and liver disease. D-mannose is the only available treatment. We report the case of a pregnant woman with MPI-CDG and the management of D-mannose therapy during pregnancy. D-mannose was discontinued at 6 weeks' gestation, due to the potential fetal toxicity observed particularly in animal models, but severe digestive symptoms and hypoglycemia relapsed. We decided to readminister D-mannose therapy at 10 weeks' gestation although data on teratogenecity in humans are lacking. Symptoms resolved rapidly when D-mannose was resumed. Monitoring of transferrin glycoforms profile and coagulation parameters allowed to gradually increase D-mannose dosage throughout pregnancy. The patient delivered at 38 weeks' gestation after an intrauterine growth retardation was noted. The infant was 2.390 kg at birth with a low Apgar score but rapidly recovered. Low dose D-mannose treatment administered from 10 weeks' gestation could be a safe option for women with MPI-CDG.
    Keywords:  D-mannose; MPI-CDG; Pregnancy; Teratogenicity
    DOI:  https://doi.org/10.1016/j.ymgme.2025.109269
  4. Carbohydr Res. 2025 Oct 24. pii: S0008-6215(25)00339-8. [Epub ahead of print]558 109713
    Human O-GlcNAc transferase substrate recognition via MALDI-TOF MS quantification of peptide glycosylation.
    Jun Bian, Yaqing Wang, Li Liu, Josef Voglmeir.
      Human O-GlcNAc transferase (hOGT) modifies serine/threonine residues on cytosolic and nuclear proteins, but predictive rules for substrate recognition are incomplete. Here, we combine MALDI-TOF MS quantification of intact peptides, conversion-based sequence logos, and molecular docking to elucidate recognition patterns. Testing a panel of synthetic peptides (7-25 residues) yielded O-GlcNAcylation from 0 % to 100 %. Stereoselective glycosylation of EA2-R produced β-O-GlcNAc (hOGT/UDP-GlcNAc), α-O-GlcNAc, and α-O-GalNAc (ppGalNAc-T2/UDP-GlcNAc or UDP-GalNAc), enabling comparative studies. Tiered analysis (≥30 %, <30 %, 0 % conversion) highlighted trends: efficient substrates prefer Pro at -2/-3, Val/Ser at -1, Ser at +1, Ala at +2, and Ser acceptors; lower groups feature reduced Pro/Val, increased acids; non-substrates show Gly at -2/-1 and poor +1/+2 residues. Targeted variants tuned reactivity (e.g., Val near -3 achieved 100 % for CKII; distal edits affected CRYAA). Docking revealed productive contacts in reactive peptides. These findings provide design rules for O-GlcNAc assays and a framework for peptide substrate engineering.
    Keywords:  Glycan modification; Glycopeptide synthesis; Glycosyltransferase; Mass spectrometry quantification; Stereoselective glycosylation
    DOI:  https://doi.org/10.1016/j.carres.2025.109713
  5. Front Pediatr. 2025 ;13 1667477
    Two case reports and a literature review of hyperphosphatasia with intellectual disability syndrome 2 caused by a PIGO mutation.
    Xinyi Wang, Jingya Zhao, Xiaoke Zhao, Le Ding, Min Zhu, Yang Li.
       Objective: This study investigates the clinical features and genetic mutations associated with hyperphosphatasia with impaired intellectual development syndrome-2 (HPIDS2).
    Methods: A retrospective analysis was performed on two HPIDS2 cases treated at the Department of Rehabilitation, Nanjing Children's Hospital, from 2019 to 2023. Clinical features and genetic characteristics were summarized through a literature review.
    Results: Genetic testing showed compound heterozygous variations in the PIGO gene for both patients (Patient 1: c.[2612A>C];[2361dup]; Patient 2: c.[2510T>A];[693C>G]), with c.[2510T>A] and c.[693C>G] identified as novel mutations.
    Conclusion: Global developmental delay, with or without hyperphosphatemia, may indicate HPIDS2. The level of alkaline phosphatase elevation could reflect disease severity and prognosis. Our cases expand the known pathogenic variations in the PIGO gene and phenotypic spectrum of HPIDS2.
    Keywords:  PIGO gene; elevated alkaline phosphatase; gene mutation; global developmental delay; hyperphosphatasia with mental retardation syndrome2
    DOI:  https://doi.org/10.3389/fped.2025.1667477
  6. Cells. 2025 Oct 14. pii: 1593. [Epub ahead of print]14(20):
    Oligosaccharyltransferase Is Involved in Targeting to ER-Associated Degradation.
    Marina Shenkman, Navit Ogen-Shtern, Chaitanya Patel, Haddas Saad, Bella Groisman, Metsada Pasmanik-Chor, Sonya M Schermann, Roman Körner, Gerardo Z Lederkremer.
      Most membrane and secretory proteins undergo N-glycosylation, catalyzed by oligosaccharyltransferase (OST), a membrane-bound complex in the endoplasmic reticulum (ER). Proteins failing quality control are degraded via ER-associated degradation (ERAD), involving retrotranslocation to cytosolic proteasomes, or relegated to ER subdomains and eliminated via ER-phagy. Using stable isotope labeling by amino acids in cell culture (SILAC) proteomics, we identified OST subunits as differential key interactors with a misfolded ER protein bait upon proteasomal inhibition, suggesting unexpected involvement in ERAD. Previous reports implied additional roles for OST subunits beyond N-glycosylation, such as quality control by ribophorin I. We tested OST engagement in glycoprotein and non-glycosylated protein ERAD; overexpression or partial knockdown of OST subunits interfered with ERAD in conditions that did not affect glycosylation. We studied the effects on model misfolded type I and II membrane-bound proteins, BACE476 and asialoglycoprotein receptor H2a, respectively, and on a soluble luminal misfolded glycoprotein, α1-antitrypsin NHK variant. OST subunits appear to participate in late ERAD stages, interacting with the E3 ligase HRD1 and facilitating retrotranslocation. Molecular dynamics simulations suggest membrane thinning by OST transmembrane domains, possibly assisting retrotranslocation via membrane distortion.
    Keywords:  ERAD; HRD1; OST; endoplasmic reticulum; retrotranslocation
    DOI:  https://doi.org/10.3390/cells14201593
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