bims-meglyc 2026-03-01 papers

bims-meglyc

Biomed News

on Metabolic disorders affecting glycosylation

Issue of 2026–03–01
seven papers selected by
Silvia Radenkovic, UMC Utrecht

Extensive Hypoglycosylation of Serum N-Glycoproteins in SRD5A3 Deficiency.
A founder variant in Tunisian PMM2-CDG patients: An integrated clinical, radiological, biochemical, and genetic study.
PGM1 deficiency is linked to sarcomeric and mitochondrial dysfunction in patient-derived iPSC-cardiomyocytes.
Glycan-related genes and genetic disorders.
Specific Detection of Sialyltransferase ST3GAL3 Towards Lipid Acceptors by Liquid Chromatography Coupled with Tandem Mass Spectrometry Indicates Total Loss of Enzyme Activity in ST3GAL3 Pathogenic Variants.
Maternal O-GlcNAc Transferase Is Required for the Asymmetry of Epigenetic Modifications in Mouse Zygotes.
Structural Characterization of Glycoprotein Glycans and Glycosaminoglycans of Brain Tissues in Slc35a3-Knockout Mice.

J Inherit Metab Dis. 2026 Mar;49(2): e70163

Extensive Hypoglycosylation of Serum N-Glycoproteins in SRD5A3 Deficiency.

Anu Jain, Rohit Budhraja, Kishore Garapati, Christina Lam, Matthew J Schultz, Tamas Kozicz, Eva Morava, Akhilesh Pandey.

  Polyprenal reductase is an enzyme encoded by the SRD5A3 gene, which is involved in the synthesis of dolichol from polyprenol. Dolichol serves as a carrier for glycan precursors or monosaccharides in N-linked glycosylation. Pathogenic variants in SRD5A3 can result in a congenital disorder of glycosylation (CDG), SRD5A3-CDG, which is inherited in an autosomal recessive manner. Most plasma proteins are glycosylated and changes in the glycosylation of several glycoproteins are associated with pathological consequences. Despite the critical role of SRD5A3 in glycosylation, the impact of its deficiency on the glycosylation of serum proteins remains largely unexplored. In this study, we used tandem mass tag-based multiplexed quantitative approach to analyze serum N-glycoproteomics and proteomics in SRD5A3-CDG patients and controls. We quantified 2200 serum N-glycopeptides from 359 N-glycosites from 204 serum proteins. Extensive hypoglycosylation of serum proteins was observed in patients, with 245 of 291 altered glycopeptides decreased in SRD5A3-CDG. Altered glycopeptides included those derived from haptoglobin, plasma serine protease inhibitor, alpha-1-B glycoprotein, alpha-2-macroglobulin, and ceruloplasmin. Some of these proteins have previously been reported to be associated with liver dysfunction, anemia, and coagulopathy, which could underlie similar clinical features observed in SRD5A3-CDG patients. Overall, our study provides novel insights into alterations in the glycosylation status of specific serum proteins in SRD5A3-CDG. Some of these alterations could be further pursued to develop glycopeptide-based biomarkers as the current diagnosis of SRD5A3-CDG by screening assays remains challenging. In addition, knowledge of altered glycoproteins could enhance our understanding of the disease spectrum and potentially unveil additional therapeutic avenues.

Keywords:  Type 1 CDG; complex glycans; polyprenol reductase; rare diseases

DOI:  https://doi.org/10.1002/jimd.70163
Mol Genet Metab. 2026 Feb 07. pii: S1096-7192(26)00049-1. [Epub ahead of print]147(4): 109766

A founder variant in Tunisian PMM2-CDG patients: An integrated clinical, radiological, biochemical, and genetic study.

Lilia Kraoua, Thouraya Ben Younes, Monia El Asmi, Abir Zioudi, Hedia Klaa, Zouhour Miladi, Hanene Benrhouma, Sonia Nagi, Sylvie Alglave, Arnaud Bruneel, Elodie Lebredonchel, Thierry Dupré, Sandrine Vuillaumier Barrot, Ichraf Kraoua.

  PMM2-CDG is the most common congenital disorder of glycosylation, characterized by a broad phenotypic spectrum involving the nervous system and multiple other organ systems. The disorder is caused by biallelic variants in the PMM2 gene, leading to impaired glycosylation of proteins. Our objective was to provide a detailed clinical characterization and define the mutational spectrum of PMM2-CDG in the Tunisian population. We conducted a retrospective study on patients with genetically confirmed PMM2-CDG, followed between 2005 and 2024. Ten patients from six unrelated Tunisian families were enrolled. All presented with neurological symptoms, including psychomotor delay (10/10), cerebellar ataxia (9/10) and strabismus (9/10). Brain MRI revealed cerebellar atrophy in all patients. Dysmorphic features were common including almond-shaped eyes (9/10), large mouth (6/10), and thin upper lip (6/10). Skeletal anomalies were observed in 9/10 patients. Peripheral neuropathy was confirmed in 6/7 patients. Laboratory analyses revealed elevated transaminases (6/10), hypocholesterolemia (7/10), elevated LDH (7/10), hypoalbuminemia (2/6), and IgA deficiency (3/5). Renal anomalies included hyperechogenicity (2/9) and a duplicated collecting system (1/9). Genetic analysis revealed a homozygous variant NM_000303.3(PMM2): c.395 T > C; p.(Ile132Thr) in all patients. Haplotype analysis of the PMM2 locus showed that all 6 families shared an identical allele. In conclusion, this is the first study to characterize the clinical and genetic profile of PMM2-CDG in the Tunisian population. Despite a shared genotype, patients exhibited moderate neurological phenotypes with inter- and intrafamilial variability. The recurrent homozygous c.395 T > C; p.(Ile132Thr) variant and identical haplotype confirm a founder effect in the Tunisian population.

Keywords:  Congenital disorder of glycosylation; Founder effect; Genotype-phenotype correlation; PMM2 gene; PMM2-CDG

DOI:  https://doi.org/10.1016/j.ymgme.2026.109766
J Transl Med. 2026 Feb 21.

PGM1 deficiency is linked to sarcomeric and mitochondrial dysfunction in patient-derived iPSC-cardiomyocytes.

Silvia Radenkovic, Graeme Preston, Rohit Budhraja, Irena Muffels, Anna Ligezka, Nathan P Staff, Ron Hrstka, Bijina Balakrishnan, Rameen Shah, Sanne Verberkmoes, Ibrahim Shammas, Inez Bosnyak, Kyle M Stiers, Kent Lai, Lesa J Beamer, Akhilesh Pandey, Eva Morava, Tamas Kozicz.

   BACKGROUND: PGM1-congenital disorder of glycosylation (PGM1-CDG) is frequently associated with cardiomyopathy. Although galactose therapy corrects glycosylation defects, cardiac dysfunction typically persists, suggesting a glycosylation-independent mechanism. Recent evidence of mitochondrial abnormalities in PGM1-deficient human and murine heart, together with the association of PGM1 with the Z-disk protein LDB3 (ZASP/Cypher), suggests a critical role for PGM1 in cardiomyocyte structural and energetic homeostasis. We hypothesized that PGM1-related cardiomyopathy arises from a glycosylation-independent disruption of Z-disk-mitochondrial coupling driven by loss of PGM1-LDB3 interactions, resulting in mitochondrial energy failure and impaired contractile function.
METHODS: Induced pluripotent stem cell-derived cardiomyocytes (iCMs) were generated from PGM1-deficient patient fibroblasts. Multielectrode array (MEA) recordings, untargeted (glyco)proteomics, and pathway analysis were performed to assess functional and molecular changes. Key findings were validated using tracer metabolomics and mitochondrial respiration assays.
RESULTS: PGM1-deficient iCMs exhibited reduced beating frequency, impaired contractility, and prolonged contraction kinetics. Proteomic analyses revealed depletion of Z-disk components, including LDB3. AlphaFold3 structural modeling predicted a direct interaction between PGM1 and LDB3, implicating PGM1 in Z-disk integrity, which was confirmed in vitro. In addition, mitochondrial proteins were severely depleted, prompting us to investigate mitochondrial function. Functional validation confirmed extensive metabolic rewiring, energy depletion, and severely impaired mitochondrial respiration. Finally, the in silico drug repurposing identified possible therapeutic options that could target PGM1-deficient cardiomyopathy.
CONCLUSION: Our data suggests PGM1 is key regulator of cardiomyocyte function, linking sarcomeric Z-disk integrity with mitochondrial metabolism. These mechanistic insights offer a foundation for developing targeted therapies for PGM1-CDG and potentially other cardiomyopathies involving Z-disk dysfunction.

Keywords:  Cardiac dysfunction; Mitochondrial dysfunction; PGM1-CDG; Phosphoglucomutase-1; Z-disk

DOI:  https://doi.org/10.1186/s12967-026-07808-9
J Hum Genet. 2026 Feb 25.

Glycan-related genes and genetic disorders.

Akira Togayachi, Kiyohiko Angata, Shoko Nishihara.

Glycosylation is a ubiquitous and essential post-translational modification in biological systems. Most cell-surface and secreted proteins are glycosylated: the glycans contribute to the structural integrity of proteins and cell membranes, and are involved in numerous physiological functions from cell-cell communication and modulation of extracellular signals to immune response and tissue development. The vast array of N-linked, O-linked, and proteoglycan-type glycans are synthesized in a stepwise manner through the coordinated action of numerous glycosyltransferases and glycosidases encoded by "glycogenes". At present, more than 400 glycogenes are involved in glycan biosynthesis in humans. Given the essential roles of glycosylation, it is not surprising that mutations in glycogenes cause various genetic disorders, collectively referred to as congenital disorders of glycosylation (CDGs). However, directly linking specific gene mutations to altered glycan structures and resulting clinical symptoms remains a significant challenge because the biological functions are mediated not by the enzymes themselves, but by the diverse glycan structures that they generate. Many undiagnosed rare diseases are suspected to result from defects in genes involved in glycosylation pathways. Furthermore, reports of newly identified types of CDGs are steadily increasing. Comprehensive understanding of these disorders requires a multidisciplinary approach integrating genetics, biochemistry, glycomics, and clinical research. In this review, we first describe glycans, including the different types and their biological functions. Next, all of the glycogenes involved in various synthetic pathways are presented, followed by examples of genetic disorders caused by their mutation and the glycogenomic approaches used to explore them.

DOI: https://doi.org/10.1038/s10038-026-01463-0
Biomedicines. 2026 Feb 12. pii: 419. [Epub ahead of print]14(2):

Specific Detection of Sialyltransferase ST3GAL3 Towards Lipid Acceptors by Liquid Chromatography Coupled with Tandem Mass Spectrometry Indicates Total Loss of Enzyme Activity in ST3GAL3 Pathogenic Variants.

Sara Penati, Michele Dei Cas, Linda Montavoci, Anna Caretti, Marco Trinchera.

  Background: Pathogenic ST3GAL3 variants cause neurological and cognitive impairment, defining a distinct congenital disorder of glycosylation (ST3GAL3-CDG). Nonetheless, limited enzyme characterization exists due to the lack of a non-radiochemical assay. Methods: Here, we developed an LC-MS/MS-based method using the artificial substrate para-nitrophenyl-lacto-N-biose (LNB-pNP; Galβ1,3GlcNAcβ1-O-C6H4NO2) to measure ST3GAL3 activity in vitro. Results: A peak corresponding to sialyl-LNB-pNP was detected in reactions with homogenate from HEK-293T cells transfected with pCDNA3 ST3GAL3 plasmid, but was virtually absent in mock-transfected cells. A substrate dependence curve provided an apparent Km value for the substrate (0.40 mM) and closely matched values from prior radiochemical methods. No activity was detected with homogenates from cells expressing pathogenic ST3GAL3 variants, except p.A13D, which is known to retain about 10% of residual activity. Compared to ST3GAL4 and ST3GAL6, ST3GAL3 showed markedly higher specificity toward LNB-pNP, lactotetraosylceramide (Lc4) and asialo-GM1, which are rather specific substrates. Instead, neo-lactotetraosylceramide (neoLc4) was processed by all three ST3GALs. Conclusions: These findings suggest that ST3GAL4 or ST3GAL6 cannot compensate for ST3GAL3 loss in the biosynthesis of gangliosides sialyl-Lc4 and GM1b, but may do so for sialyl-neoLc4. This non-radiochemical assay enables screening and diagnostic evaluation of novel ST3GAL3 variants potentially associated with ST3GAL3-CDG.

Keywords:  congenital disorder of glycosylation; ganglioside; glycosphingolipid; sialylation

DOI:  https://doi.org/10.3390/biomedicines14020419
FASEB J. 2026 Feb 28. 40(4): e71592

Maternal O-GlcNAc Transferase Is Required for the Asymmetry of Epigenetic Modifications in Mouse Zygotes.

Haoxue Wang, Dan Liu, Shinnosuke Honda, Shuntaro Ikeda.

  After fertilization in mammals, there is an epigenetic asymmetry reflected by differences in DNA demethylation and histone modifications between female and male pronuclei (FPN and MPN, respectively). Based on its expression level and amount, we investigated the role of maternal O-GlcNAc transferase (OGT), a key enzyme mediating O-GlcNAcylation, in regulating this asymmetry. By using a specific small-molecule inhibitor and small interfering RNA (siRNA)-mediated knockdown of OGT during oocyte maturation in mice, we evaluated the downstream effects on epigenetic modifications and early developmental capability. OGT inhibition significantly reduced fertilization rates and led to developmental arrest at the zygote or 2-cell stage, whereas the siRNA-mediated decrease of Ogt mRNA had less or no significant effect on preimplantation development. Immunostaining analyses revealed that OGT inhibition reduced 5-hydroxymethylcytosine levels in MPN, attributed to a reduction in Tet methylcytosine dioxygenase 3. In contrast, FPN showed delayed epigenetic changes, with the loss of 5-methylcytosine protection mediated by H3K9me2. Moreover, OGT inhibition increased histone methylation levels in MPN and disrupted epigenetic and size asymmetry between FPN and MPN. These alterations suggest that maternal OGT regulates multiple layers of epigenetic reprogramming in early zygotes. Taken together, these findings suggest that maternal OGT is essential for maintaining epigenetic asymmetry between parental pronuclei, primarily by modulating DNA demethylation and histone methylation in MPN.

Keywords:  DNA demethylation; O‐GlcNAc transferase; embryonic development; epigenomics; histone; oocyte; zygote

DOI:  https://doi.org/10.1096/fj.202503577RR
Int J Mol Sci. 2026 Feb 08. pii: 1643. [Epub ahead of print]27(4):

Structural Characterization of Glycoprotein Glycans and Glycosaminoglycans of Brain Tissues in Slc35a3-Knockout Mice.

Ikumi Hirose, Hisatoshi Hanamatsu, Shuji Mizumoto, Rina Yamashita, Shuhei Yamada, Jun-Ichi Furukawa, Tatsuya Furuichi, Hirokazu Yagi.

  Glycosylation depends on luminal nucleotide sugars delivered by solute carrier 35 (SLC35) transporters. SLC35A3 is a uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) transporter. In humans, biallelic mutations in SLC35A3 cause arthrogryposis, mental retardation, and seizures (AMRS). To define how loss of SLC35A3 function reshapes the neural glycome, we profiled N-, O-, and glycosaminoglycans (GAGs) in Slc35a3 knockout mouse brains. N- and O-glycans were analyzed by MALDI-TOF MS, and GAG disaccharides were quantified by anion-exchange HPLC. Knockout mouse brains exhibited attenuation of complex-type N-glycans with a reciprocal rise in high-mannose species, as revealed by MALDI-TOF MS profiling. In contrast, ConA lectin blotting showed no significant change, consistent with its preferential detection of mannose-rich glycans. Branching analysis revealed loss of tri- and tetra-antennary structures compared with biantennary species. O-glycan profiling showed core-2-type species (Hex2HexNAc2 backbone) decreased. The dominant disialyl core-1 remained stable. Total GAG output (chondroitin/dermatan sulfate, heparan sulfate, and hyaluronan) was preserved. These findings support a microdomain model in which SLC35A3 acts as a locally effective supplier of UDP-GlcNAc to MGAT4 (branching N-acetylglucosaminyltransferase that installs the β1,4-GlcNAc arm) in the brain, while alternative routes buffer UDP-GlcNAc delivery for GAG and mucin-type O-glycan biosynthesis. Accordingly, AMRS may be attributed to impaired higher-order N-glycan branching in the brain.

Keywords:  Core-2 O-glycan (GCNT1/C2GnT); MALDI-TOF-MS; MGAT4-dependent N-glycan branching; SLC35A3; UDP-GlcNAc transporter; glycosaminoglycan

DOI:  https://doi.org/10.3390/ijms27041643