bims-meglyc Biomed News
on Metabolic disorders affecting glycosylation
Issue of 2026–02–08
twelve papers selected by
Silvia Radenkovic, UMC Utrecht
  1. Repurposing the HMG-CoA Reductase Inhibitor Atorvastatin for SRD5A3-CDG.
  2. Congenital disorder of deglycosylation 2. Report of a novel MAN2C1 pathogenic variant and additional phenotypic implications.
  3. The Role of Pyridoxine Treatment for Seizures in Patients with PGAP3-Congenital Disorders of Glycosylation.
  4. Feeding-regulated glycogen metabolism drives rhythmic liver protein secretion.
  5. GNE-related thrombocytopenia (Thrombocytopenia-12) in a 3-month-old from a Middle Eastern background infant: a case report.
  6. Mannose metabolic pathway senses glucose supply and regulates cell fate decisions.
  7. Clinical and biochemical footprints of primary mitochondrial disorders: proposed nosology.
  8. The TRAP complex (SSR1-SSR4): mechanistic roles and therapeutic opportunities.
  9. Subclinical Respiratory Muscle Weakness and Obstructive Sleep Apnea are Common in Glucosamine-UDP-N-acetyl-2-epimerase / N-acetylmannosamine kinase (GNE) Myopathy.
  10. The HCF-1:OGT axis regulates neuronal proliferation and differentiation.
  11. Phase 1 Study of Oral N-Acetylmannosamine in Primary Podocytopathies.
  12. Transcript-Level Modulation of O-GlcNAc Transferase for Aging-Related Neurodegenerative Diseases.
  1. bioRxiv. 2026 Jan 20. pii: 2026.01.18.699766. [Epub ahead of print]
    Repurposing the HMG-CoA Reductase Inhibitor Atorvastatin for SRD5A3-CDG.
    Hiba Daghar, Seul Kee Byeon, Claudia Maios, Jennifer Poon, James J Doyle, Wasantha Ranatunga, Éric Samarut, Ethan O Perlstein, Eva Morava, Akhilesh Pandey, J Alex Parker, Kristin A Kantautas.
      SRD5A3-CDG is a rare autosomal recessive congenital disorder of glycosylation characterized by multisystemic dysfunction, including neurological, psychomotor, cognitive, and visual impairments. Approximately 60 cases have been reported, with treatment limited to symptomatic management. SRD5A3 encodes a polyprenal reductase enzyme essential for synthesizing dolichol, a lipid carrier of the oligosaccharide precursor in N-glycosylation. To address the lack of effective treatments and disease models suitable for high-throughput screening, we developed the first C. elegans model of SRD5A3-CDG, harboring the homozygous W19X nonsense mutation commonly observed in patients. This model recapitulates disease-relevant phenotypes, including developmental delays, neurological dysfunction, and mevalonate pathway dysregulation. Using this model, we conducted a high-throughput motility-based drug repurposing screen and identified atorvastatin, an FDA-approved HMG-CoA reductase inhibitor, as a repurposing candidate. Atorvastatin rescued disease-relevant phenotypes in the worm model and restored polyprenol-to-dolichol ratios in patient fibroblasts. These findings highlight atorvastatin as a promising drug repurposing candidate for SRD5A3-CDG.
    DOI:  https://doi.org/10.64898/2026.01.18.699766
  2. Mol Genet Metab Rep. 2026 Mar;46 101289
    Congenital disorder of deglycosylation 2. Report of a novel MAN2C1 pathogenic variant and additional phenotypic implications.
    Rafael Luis Aguirre-Guillen, Luis Ángel Arredondo-Navarro, María Fernanda Hernández-Rodríguez, Martín-De La Torre Eduardo, Contreras Peregrina María Del Rosario, Mayra Alejandra Arce-Lozoya, Estefanía Ochoa-Padilla, Víctor Ulises Rodríguez-Machuca.
      The MAN2C1 gene encodes an enzyme with alpha-mannosidase 2C1 activity, which is responsible for the degradation of defective glycoproteins in the cytoplasm. The purpose of this report is to present a novel MAN2C1 pathogenic variant in a patient with a congenital disorder of deglycosylation 2. We describe a case with 15q24.1q24.3 microdeletion syndrome which also presented a deleterious variant in the MAN2C1 gene located at the opposite allele. We discussed the phenotypic consequences when MAN2C1 gene transcript is missing.
    Keywords:  15q24.1q24.3 microdeletion; Congenital hydrocephalus; Deglycosylation disorder; MAN2C1
    DOI:  https://doi.org/10.1016/j.ymgmr.2026.101289
  3. Ann Indian Acad Neurol. 2026 Jan 31.
    The Role of Pyridoxine Treatment for Seizures in Patients with PGAP3-Congenital Disorders of Glycosylation.
    Şeyda Beşen, Yasemin Özkale, Özlem Sangün, İlknur Erol.
       ABSTRACT: Hyperphosphatasia with mental retardation syndrome (HPMRS) is a rare genetic disorder characterized by developmental delay/intellectual disability, seizures, dysmorphic features, and diverse congenital anomalies with elevated alkaline phosphatase. It is an autosomal recessive disease caused by homozygous or compound heterozygous mutations in the PIGV, PIGY, PIGO, PGAP2, PIGW, and PGAP3 genes, which are involved in glycosylphosphatidylinositol biosynthesis. Mutations in the PGAP3 gene cause HPMRS type 4.
    Keywords:  Hyperphosphatasia; PGAP3 global developmental delay; epilepsy; pyridoxine treatment
    DOI:  https://doi.org/10.4103/aian.aian_830_25
  4. Nat Metab. 2026 Feb 05.
    Feeding-regulated glycogen metabolism drives rhythmic liver protein secretion.
    Meltem Weger, Daniel Mauvoisin, Dominic Hoyle, Jingkui Wang, Eva Martin, James Rae, Charles Ferguson, Glynis Klinke, Michelle Cielesh, Kyle L Macauslane, Mark Larance, Manfredo Quadroni, Iain Templeman, Jean-Philippe Walhin, Leonidas G Karagounis, James A Betts, Jonathan D Johnston, Fanny Durussel, Dmitri Firsov, Stephane Fournier, Olivier Müller, Benjamin L Schulz, Robert G Parton, Benjamin D Weger, Frédéric Gachon.
      The liver has a key role in inter-organ communication by secreting most circulating plasma proteins. However, the mechanisms governing hepatic protein secretion remain unclear. Here we show that hepatic protein secretion follows a diurnal rhythm regulated by food intake in humans and mice. Using liver microsomal proteomics, we find that proteins implicated in the early secretory pathway, such as protein glycosylation and folding in the endoplasmic reticulum (ER) and Golgi apparatus, exhibit a rhythmic expression profile, which is abolished in Bmal1-knockout mice. Mechanistically, we show that hepatic glycogenolysis provides substrates for protein N-glycosylation. In mice, perturbing hepatic glycogenolysis with pharmacological or nutritional interventions leads to ER stress and attenuates diurnal protein secretion. We confirm these results in humans, as genetic variants associated with glycogen storage disease and congenital disorders of glycosylation also alter hepatic protein secretion. Overall, our work uncovers hepatic glycogen metabolism as a circadian regulator of protein secretion.
    DOI:  https://doi.org/10.1038/s42255-026-01453-8
  5. Hematology. 2026 Dec;31(1): 2620148
    GNE-related thrombocytopenia (Thrombocytopenia-12) in a 3-month-old from a Middle Eastern background infant: a case report.
    Omar Ahmed Alshaikhi, Elaf Yahia Faraj Alnasser.
       BACKGROUND: Congenital thrombocytopenia represents a diagnostically challenging group of disorders due to overlapping clinical presentations among various etiologies.
    CASE PRESENTATION: A 3-month-old infant presented with severe thrombocytopenia (platelet count 6,000/μL), neutropenia, and bone marrow findings of megakaryocytic hypoplasia, initially suggestive of congenital amegakaryocytic thrombocytopenia (CAMT). Comprehensive genetic testing identified a homozygous pathogenic variant in the GNE gene (NM_001128227.2:c.1768G > A, p.Gly590Arg), establishing the definitive diagnosis of GNE-related thrombocytopenia (Thrombocytopenia-12, THC12).
    CLINICAL SIGNIFICANCE: This case highlights three critical aspects: first, the essential role of genetic testing in differentiating congenital thrombocytopenias; second, the distinct management implications of THC12 compared to CAMT; and third, the need for long-term monitoring given the potential for late-onset myopathy despite initial isolated hematologic manifestations.
    MANAGEMENT: Therapeutic interventions included intravenous immunoglobulin, platelet transfusions, and thrombopoietin receptor agonists, with concurrent evaluation for potential hematopoietic stem cell transplantation.
    CONCLUSION: This report underscores THC12 as an important diagnostic consideration in infants with congenital thrombocytopenia and emphasizes the necessity of genetic confirmation to guide appropriate clinical management and family counseling.
    Keywords:  GNE gene mutation; GNE-related thrombocytopenia; Thrombocytopenia-12 (THC12); congenital thrombocytopenia; glycosylation disorder; platelet hyposialylation; thrombopoietin receptor agonist (TPO-RA); whole-exome sequencing (WES)
    DOI:  https://doi.org/10.1080/16078454.2026.2620148
  6. J Biol Chem. 2026 Jan 28. pii: S0021-9258(26)00083-9. [Epub ahead of print] 111213
    Mannose metabolic pathway senses glucose supply and regulates cell fate decisions.
    Ziwei Wang, Yasuhide Miyamoto, Takehiro Suzuki, Miki Tanaka-Okamoto, Yu Mizote, Naoshi Dohmae, Hideaki Tahara, Naoyuki Taniguchi, Yoichiro Harada.
      Mammalian cells exploit diverse metabolic pathways to regulate cell fates during glucose deprivation. We previously reported that glucose deprivation lowers the metabolic activity of mannose pathway that is interconnected with glycolysis, leading to biosynthetic arrest and degradation of the glycan precursors for asparagine-linked glycosylation (N-glycosylation) in the endoplasmic reticulum (ER). However, the cellular role of this sequential metabolic response remains unknown, largely due to metabolic complications caused by glucose deprivation. Here, we genetically engineered cells to separate mannose pathway from glycolysis, allowing precise control of mannose pathway activity by adjusting mannose supply levels instead of changing glucose supply. Moderate decrease in mannose supply severely suppressed N-glycosylation, leading to activation of pro-survival PERK-eIF2 signals. Although further decrease in mannose supply to the minimal levels did not compromise cell survival, it depleted luminal protective glycocalyx of lysosomes and increased a risk of cell death by impairing lysosome integrity. These results indicate that low metabolic flux of glucose into mannose pathway initiates alterations in homeostasis of the ER and lysosomes, at least in part through N-glycosylation defects, leading to cell fate decisions.
    Keywords:  Cell fate decision; N-glycosylation; endoplasmic reticulum; glucose deprivation; lysosomes
    DOI:  https://doi.org/10.1016/j.jbc.2026.111213
  7. Mol Genet Metab. 2025 Dec 11. pii: S1096-7192(25)00696-1. [Epub ahead of print]147(3): 109704
    Clinical and biochemical footprints of primary mitochondrial disorders: proposed nosology.
    Martina Messina, Rebecca Ganetzky, Carlos R Ferreira, Nenad Blau, Shamima Rahman.
      Primary mitochondrial diseases (PMD) are a growing number of disorders caused by mitochondrial dysfunction. There is not yet a consensus on the precise definition of PMD. Therefore, this study presents an approach to developing a nosology for standardized, systematic classification of PMD, harmonized with ICIMD and IEMbase. A total of 452 PMD causative genes were included. The classification includes 18 categories: 1) Disorders of amino acid metabolism; 2) Disorders of peptide and amine metabolism; 3) Disorders of carbohydrate metabolism; 4) Disorders of fatty acid and ketone body metabolism; 5) Disorders of energy substrate metabolism; 6) Mitochondrial DNA-related disorders; 7) Nuclear-encoded disorders of oxidative phosphorylation; 8) Disorders of mitochondrial cofactor biosynthesis; 9) Disorders of mitochondrial DNA maintenance and replication; 10) Disorders of mitochondrial gene expression; 11) Other disorders of mitochondrial function; 12) Disorders of metabolite repair/proofreading; 13) Disorders of lipid metabolism; 14) Disorders of nucleobase, nucleotide and nucleic acid metabolism; 15) Disorders of tetrapyrrole metabolism; 16) Disorders of organelle biogenesis, dynamics and interaction; 17) Disorders of vitamin and cofactor metabolism and 18) Neurotransmitter disorders. We also describe the clinical involvement of 22 organs and systems and laboratory features. The most prevalent symptoms (per gene) were neurological (21.1%), ocular (10.3%), muscular (9.0%), gastrointestinal (8.3%), and cardiovascular (7.9%).
    Keywords:  Biomarkers; ICIMD; IEMbase; Inherited metabolic disorders; Signs and symptoms
    DOI:  https://doi.org/10.1016/j.ymgme.2025.109704
  8. Ann Med. 2026 Dec;58(1): 2624859
    The TRAP complex (SSR1-SSR4): mechanistic roles and therapeutic opportunities.
    Jiaqi Zhang, Xing Wan, Aixia Gong.
       BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is a highly aggressive cancer with a poor prognosis, and its molecular mechanisms remain unclear. Our previous research identified the signal sequence receptor subunit delta (SSR4) of the TRAP complex as a potential ESCC biomarker. The TRAP complex, composed of SSR1, SSR2, SSR3, and SSR4, is essential for protein translocation, folding, and quality control, crucial for cellular balance. While individual TRAP subunits have been studied, a comprehensive understanding of their roles in human diseases is lacking.
    AIM: This review synthesizes current evidence on the TRAP complex and its subunits (SSR1-SSR4) to clarify their roles in tumor progression and other diseases, identify knowledge gaps, and evaluate their potential as therapeutic targets.
    RESULTS: The study shows that TRAP subunit genes are significantly upregulated in various cancers, influencing tumor progression and immune infiltration, with some subunits showing different responses to chemotherapy. A pan-cancer analysis highlights their roles, while SSR3 and SSR4 mutations are linked to congenital glycosylation disorders. SSR1 and SSR3 are essential for glucose metabolism and are associated with diabetes risk. The interaction between TRAP and endoplasmic reticulum stress suggests potential therapeutic applications.
    CONCLUSION: This review emphasizes the crucial roles of the TRAP complex and its subunits (SSR1-SSR4) in various diseases, highlighting their potential as therapeutic targets and biomarkers. Future research should focus on understanding the mechanisms through integrated experimental and multi-omics approaches, defining subunit interactions, and exploring structure-based drug design for clinical applications.
    Keywords:  SSR1; SSR2; SSR3; SSR4; TRAP complex
    DOI:  https://doi.org/10.1080/07853890.2026.2624859
  9. Ann Indian Acad Neurol. 2026 Feb 03.
    Subclinical Respiratory Muscle Weakness and Obstructive Sleep Apnea are Common in Glucosamine-UDP-N-acetyl-2-epimerase / N-acetylmannosamine kinase (GNE) Myopathy.
    Esen Kiyan, Aylin Pihtili, Hacer Durmus, Yesim Parman.
       ABSTRACT: Glucosamine-UDP-N-acetyl-2-epimerase / N-acetylmannosamine kinase (GNE) myopathy is a rare, slowly progressive myopathy primarily affecting distal muscles. Limited evidence suggests possible respiratory muscle weakness and obstructive sleep apnea (OSA). We aimed to assess daytime lung functions and OSA in GNE myopathy. Nine patients were evaluated by spirometry, maximal inspiratory pressure (MIP), maximal expiratory pressure, single-breath count (SBC), peak cough flow (PCF), arterial blood gases (ABG), sleep questionnaires, and polysomnography. All patients had normal spirometry and ABGs, but 55.6% had decreased MIP, 44.4% had decreased PCF, and 55.6% had SBC<20. Poor sleep quality was common (77.8%). OSA was present in 66.7% of the patients. In conclusion, subclinical respiratory muscle weakness and OSA were frequent in GNE myopathy patients with normal spirometry. Therefore, MIP, PCF, SBC, and polysomnography should be included in routine evaluation.
    Keywords:  GNE myopathy; obstructive sleep apnea; polysomnography; respiratory muscle weakness
    DOI:  https://doi.org/10.4103/aian.aian_725_25
  10. Neurobiol Dis. 2026 Feb 04. pii: S0969-9961(26)00052-5. [Epub ahead of print] 107308
    The HCF-1:OGT axis regulates neuronal proliferation and differentiation.
    Ayushma, Priyanka Prakash Srivastava, Shruti Kaushal, Jaspreet K Dhanjal, Vaibhav Kapuria, Shilpi Minocha.
      Neuronal differentiation requires precise coordination of progenitor proliferation, lineage commitment, and chromatin regulation to establish functional brain architecture. Host Cell Factor-1 (HCF-1), an X-linked transcriptional co-regulator linked to human intellectual disability, is essential for early development, yet its lineage-specific roles during mammalian neurogenesis remain incompletely defined. Here, we investigate the function of the HCF-1-OGT axis during neuronal differentiation and forebrain development. Early embryonic loss of HCF-1 resulted in developmental arrest due to gastrulation defects, while conditional deletion in Nkx2.1-derived neuronal lineages caused pronounced cortical disorganization, reduced GABAergic interneuron survival, and severe defects in forebrain commissures, including the corpus callosum and anterior commissure. These abnormalities were not observed following glial-restricted deletion, indicating a neuron-specific requirement for HCF-1. Neuronal ablation alone did not phenocopy these defects; however, combined neuronal ablation and HCF-1 loss exacerbated cortical and commissural abnormalities, revealing increased neuronal vulnerability. Transcriptomic profiling following HCF-1 depletion identified widespread dysregulation of gene networks associated with neuronal differentiation, synaptic organization, chromatin regulation, and axon guidance. Consistently, HCF-1 directly occupied promoters of key neuronal genes, including Elavl3 and NeuroD1, and its loss reduced activating chromatin marks at these loci. In vitro, depletion of HCF-1 or inhibition of OGT impaired neuronal proliferation, differentiation, and neurite outgrowth. Glycoproteomic analysis further revealed disruption of OGT-dependent protein networks involved in neuronal structure and maturation. Together, these findings identify HCF-1 as a central regulator of neuronal differentiation and forebrain organization and provide mechanistic insight into how disruption of the HCF-1-OGT axis contributes to neurodevelopmental disorders.
    Keywords:  Differentiation; HCF-1; Host cell factor 1; Neurons; Nkx2.1; O-linked N-acetylglucosamine transferase; OGT
    DOI:  https://doi.org/10.1016/j.nbd.2026.107308
  11. Kidney Int Rep. 2026 Mar;11(3): 103758
    Phase 1 Study of Oral N-Acetylmannosamine in Primary Podocytopathies.
    NIH-ManNAc Study Team
       Introduction: Terminal sialic acid (SA) residues on glycoconjugates are essential for maintaining the glomerular filtration barrier's charge selectivity and podocyte ultrastructure. SA depletion affects key podocyte glycoproteins, contributing to podocytopathy and proteinuria. Glomerular hyposialylation is commonly seen in experimental podocytopathies and human renal biopsies. In nephrotic mouse models, oral administration of the metabolic SA precursor, N-acetylmannosamine (ManNAc) restored sialylation and reduced proteinuria, suggesting therapeutic potential.
    Methods: In this single-center, single-arm, ascending dose phase 1 trial, we evaluated safety and pharmacokinetics (PKs) of oral ManNAc in primary podocytopathies (ClinicalTrials.gov: NCT02639260). Eligible participants had urine protein-to-creatinine ratio (UPCR) > 1 g/g and estimated glomerular filtration rates (eGFR) > 15 ml/min per 1.73 m2. Six subjects received a single 3g ManNAc dose followed by 5 days of 1.5 g twice-daily (BID) dosing. One subject received a single 6 g dose.
    Results: All enrolled participants had primary podocytopathy, with eGFR of 25 to 89 ml/min per 1.73 m2 and UPCR of 1.1 to 9.21 g/g. ManNAc was well-tolerated without serious adverse events (AEs). Maximum plasma ManNAc concentration was reached within 2 to 4 hours postdose, with dose-dependent increases in plasma SA. Subjects with eGFR < 45 ml/min per 1.73 m2 showed elevated maximum plasma ManNAc concentration and area under curve for both ManNAc and SA, reflecting reduced renal clearance. Proteinuria reduction of 12% to 52% (regression-adjusted mean 9.69%, P < 0.0001) was observed in subjects receiving ManNAc BID, correlating with glomerular hyposialylation in pre-study renal biopsies.
    Conclusion: Oral ManNAc demonstrated short-term safety and increased plasma SA levels in podocytopathy subjects. Early efficacy signals suggest that proteinuria reduction may correlate with glomerular hyposialylation, identifying a potential treatment biomarker. A phase 2 trial (NCT06664814) is underway to assess long-term outcomes.
    Keywords:  N-acetylmannosamine (ManNAc); phase 1 trial; podocytopathy; proteinuria; sialylation
    DOI:  https://doi.org/10.1016/j.ekir.2025.103758
  12. Chembiochem. 2026 Jan;27(2): e202500774
    Transcript-Level Modulation of O-GlcNAc Transferase for Aging-Related Neurodegenerative Diseases.
    Florian Malard.
      The O-GlcNAc Transferase (OGT) is responsible for the addition of β-O-linked N-acetyl-D-glucosamine (O-GlcNAc) to serine and threonine residues, thereby regulating more than 8000 human proteins through O-GlcNAcylation. In the brain, reduced O-GlcNAc levels, which can arise from insufficient OGT activity, have been increasingly linked to aging-related neurodegenerative diseases such as Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis. While current strategies focus on restoring O-GlcNAc levels via O-GlcNAcase (OGA) inhibition, recent discoveries highlight transcript-level regulation of OGT as a direct and promising therapeutic target. This concept article explores the role of intron detention and decoy exon-mediated splicing repression in limiting OGT pre-mRNA maturation and proposes the use of antisense oligonucleotides or selective splicing factor degraders to promote productive splicing and nuclear export of OGT mRNA. By enhancing OGT expression independently of O-GlcNAc feedback, these approaches aim to restore proteostasis and improve resilience to neurodegeneration, offering a novel therapeutic approach for aging-related neurodegenerative diseases.
    Keywords:   O‐GlcNAc transferase; O‐GlcNAcylation; RNA therapeutics; alternative splicing; antisense oligonucleotide; neurodegenerative diseases
    DOI:  https://doi.org/10.1002/cbic.202500774
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