bims-meglyc 2026-11-01 papers

Issue of 2026–11–01
five papers selected by
Silvia Radenkovic, UMC Utrecht

Transfusion. 2026 Oct 26.

A PIGG congenital disorder of glycosylation (PIGG-CDG) variant associated with an Emm- red blood cell phenotype in a pediatric patient.

Alastair Murray, Connie M Westhoff, Sunitha Vege, Hallie Lee-Stroka, Randall W Velliquette, William J Lane, Jillian G Buchan, Nabiha H Saifee, Rida A Hasan.

BACKGROUND: The high-prevalence Emm antigen is an epitope on the GPI (glycosylphosphatidylinositol) glycolipid backbone, which anchors proteins to the cell surface. Inherited loss-of-function of PIGG (or PIGO) results in the rare Emm- red cell (RBC) phenotype and is associated with congenital disorders of glycosylation (CDG). Anti-Emm has been reported to cause clinically significant hemolytic transfusion reactions.
CASE PRESENTATION: We describe a 2-year-old male with neurologic manifestations of CDG in whom whole-exome sequencing (WES) identified a homozygous PIGG c.1515G>A, p.(Trp505Ter) variant. The patient had received a single RBC transfusion in infancy with no detectable alloantibodies. Serologic evaluation demonstrated an Emm- RBC phenotype. Confirmation by Sanger sequencing verified homozygosity for this PIGG loss-of-function variant, and family studies showed both parents and a sibling were heterozygous.
DISCUSSION: To date, eight other PIGG variants are known to underlie the Emm- phenotype; the c.1515G>A, p.(Trp505Ter) variant has not previously been shown to cause a null phenotype. Recognition of the rare Emm- phenotype in patients with CDG has important transfusion implications, including alloimmunization risk and difficulty sourcing compatible blood due to the rare occurrence and lack of typing reagents.
CONCLUSION: This case expands the number of PIGG variants associated with the Emm- phenotype and underscores the importance of integrating the growing number of genomic diagnostic findings with transfusion medicine evaluation to guide safe transfusion management.

DOI: https://doi.org/10.1111/trf.70450

Mol Genet Metab Rep. 2026 Dec;49 101375

Longitudinal analysis of clinical and biochemical outcomes during seven years of galactose supplementation in a patient with SLC35A2-CDG.

Yupeng Liu, Earnest J P Daniel, Wenyue Zhang, Andrew Edmondson, Miao He.

Background: SLC35A2-CDG is a rare X-linked congenital disorder of glycosylation caused by impaired UDP-galactose transport into the Golgi apparatus, resulting in multisystem involvement with prominent neurological manifestations. Although oral galactose supplementation has been proposed as a targeted therapy, its long-term efficacy and safety remain unclear.
Methods: We report a longitudinal study of a female patient with SLC35A2-CDG treated with oral D-galactose supplementation over seven years. Clinical outcomes were assessed using the Nijmegen Pediatric CDG Rating Scale (NPCRS), and glycosylation abnormalities were monitored via N-glycomics profiling. Glycosylation biomarkers associated with clinical severity were subsequently applied retrospectively to evaluate eight additional SLC35A2-CDG patients with absent or uncertain responses to galactose therapy.
Results: Our index patient demonstrated significantly clinical and biochemical improvements, with the NPCRS score improving from 22 to 12. Plasma N-glycan profiling showed improvement and normalization in both under-galactosylated glycans and normally formed disialylated glycans. Fractionated N-glycan analysis confirmed consistent improvement in both affinity-purified transferrin and the triple-depleted plasma fraction with IgG, transferrin and albumin removed. Strong correlations were also identified between glycosylation markers and disease severity. In contrast, seven non-responder patients showed no obvious clinical or biochemical response, while one displayed partial biochemical improvement and steady clinical course.
Conclusions: This study provides the first long-term evidence that galactose supplementation is effective with meaningful clinical and biochemical improvement observed in a SLC35A2-CDG patient. Glycosylation profiling may serve as a supportive tool for monitoring treatment response and guiding individualized therapy.

Keywords: CDG; Galactose; Glycosylation; N-glycan; SLC35A2

DOI: https://doi.org/10.1016/j.ymgmr.2026.101375

Int J Mol Sci. 2026 Oct 12. pii: 9032. [Epub ahead of print]27(20):

From Prediction to Generation: Artificial Intelligence Reconstructing the Paradigm of Protein Glycosylation Research.

Junhong Zhu, Shuang Huang, Nannan Zhang.

Among post-translational modifications, protein glycosylation is distinguished by its abundance and structural intricacy. Unlike protein biosynthesis, glycan assembly follows no template; it reflects glycosyltransferase/glycosidase competition, sugar-donor availability, and organelle-enforced compartmentalization, yielding heterogeneous glycoforms that confer functional versatility but complicate analysis. Three bottlenecks persist: stereochemical control in chemical glycosylation, ambiguous assignment of occupancy sites, and reproducing native conformations of fully glycosylated proteins. Adopting the "glycan language" framework, we survey how AI addresses each, emphasizing the systems on which it has been tested. In synthesis planning, GlycoPredictor uncovered anomeric-selectivity rules such as the anti-nitrile and C2-azido α-directing effects, while Bayesian optimization discovered lithium-salt-directed stereoselective glycosylation; for site identification, ESM-2 with AlphaFold2-derived structural features improves N- and O-glycosite prediction, and DeepGlycanSite maps carbohydrate-binding interfaces. For structure and dynamics, AlphaFold3 and multimodal cryo-electron microscopy (cryo-EM), hydrogen-deuterium exchange mass spectrometry, and molecular dynamics (MD) modeling move glycoproteins toward conformational ensembles, as in the AI-assisted dissection of the MCTS1-JAK2-IFN-γ axis. In glycomics, deep learning resolves intact glycopeptides and de novo glycan topology and has defined Fc N-glycan signatures of immunoglobulin G in autoimmune and malignant disease. Because glycan language models link sequence and structure to function, they are becoming clinically actionable: they prioritize candidate variants in congenital disorders of glycosylation and stratify immune disorders and tumors by aberrant glycosylation. Remaining obstacles include scarce structure-linked datasets, encoding of branched topologies, multimodal fusion, and interpretability.

Keywords: artificial intelligence; glycan language; glycoengineering; glycoprotein structure; glycosite prediction; protein glycosylation; protein language model

DOI: https://doi.org/10.3390/ijms27209032

Front Cell Dev Biol. 2026 ;14 1966226

Genotype-specific molecular and functional trajectories in NGLY1 deficiency: a comparative multi-omics study of patient-derived iPSC neurons.

Soukaina Amniouel, Zeenat A Shyr, William F Borschel, Mitali Tambe, Atena Farkhondeh, Wei Zheng.

Background: NGLY1 deficiency is an ultra-rare congenital disorder of deglycosylation with prominent neurodevelopmental impairment and marked allelic heterogeneity. Prior human neuronal models have characterized NGLY1 loss largely within single genetic backgrounds, leaving open whether distinct patient genotypes converge on a shared molecular state or follow divergent routes. Because clinical presentations overlap across genotypes, resolving this question requires a direct, within-system comparison of multiple genotypes rather than characterization of any single line.
Methods: We generated iPSC-derived glutamatergic neurons from three patients carrying distinct biallelic NGLY1 genotypes (R401X/R401X, Q208X/G310G, L318P/R390P) and two healthy controls, and profiled them head-to-head using matched transcriptomics and proteomics at day 28, RNA to protein concordance and differential exon usage analysis, pathway and phenotype network integration, and longitudinal multielectrode array (MEA) recordings during early network maturation.
Results: Across both molecular layers, samples segregated strongly by genotype rather than forming a unified disease signature. Differential expression revealed pronounced between-genotype heterogeneity with only a small shared molecular core. RNA to protein concordance was moderate and genotype-dependent, and differential exon usage was enriched among discordant genes in a mutation-dependent manner, implicating splicing-level regulation in the transcript to protein divergence. Integrated networks linked genotype-specific concordant changes to synaptic signaling, calcium handling, metabolism, and extracellular matrix remodeling, and connected them to overlapping clinical phenotypes through distinct molecular routes. MEA recordings showed delayed maturation and genotype-dependent shifts in network excitability, with functional clustering that mirrored the molecular separation.
Conclusion: Distinct NGLY1 genotypes produce divergent molecular and functional trajectories that converge on impaired network maturation through non-identical routes. These findings reframe NGLY1 deficiency as a set of genotype-specific molecular states rather than a single phenotype, with direct implications for mechanistic subgrouping and the design of preclinical models and validation studies.

Keywords: NGLY1 deficiency; genotype-specific biomarkers; induced pluripotent stem cells; multi-omics; multielectrode array; proteomics; rare diseases; transcriptomics

DOI: https://doi.org/10.3389/fcell.2026.1966226

Proc Natl Acad Sci U S A. 2026 Nov 03. 123(44): e2621329123

Structural basis of glycoprotein recognition by the human folding sensor UDP-glucose:glycoprotein glucosyltransferase.

David Aparicio, Juan R Ortigosa, Kevin P Guay, Robert V Williams, Jorge O Lannot, Guanghui Zong, Natalia Comino, José F Rodríguez, Lai-Xi Wang, Marcelo A Martí, Pietro Roversi, Daniel N Hebert, Lila M Gierasch, Carlos P Modenutti, Marcelo E Guerin.

UDP-glucose:glycoprotein glucosyltransferase 1 (UGGT1) plays a central role in quality control of glycoprotein folding within the early secretory pathway, yet the molecular basis of UGGT1 substrate recognition remains poorly understood. Here, we report cryo-EM structures of human full-length multidomain UGGT1. Monomeric UGGT1 structures reveal two conformational states corresponding to "open" and "closed" architectures. Three-dimensional variability and molecular dynamics simulations suggest the existence of intermediate conformations, leading to a model in which a continuum of structural transitions underlies UGGT1 function. Notably, in the open state, the EM-maps reveal at the top of the U-shaped protein a density that bridges the sensory TRXL2 and the glucosyltransferase catalytic domains, consistent with substrate association. This observation supports a mode of binding that places the substrate near the catalytic domain. A dimeric form of UGGT1 was observed in which the glycoprotein substrate binding sites are occluded, suggesting that dimerization may regulate UGGT1 activity. To better understand the spatial relationship between the site of misfolding and that of UGGT-mediated N-glycan reglucosylation, we identified N-glycosylation sites on endogenous glycoprotein substrates by glycoproteomics. No consensus sequence was found flanking modified sites, indicating that substrate recognition relies on mechanisms beyond primary sequence. Mutations in the UGGT1 gene cause a novel congenital disorder of glycosylation characterized by developmental delay and intellectual disability, and the human UGGT1 structure helps explain how disease-associated missense and deletion variants disrupt function. Together, our data provide insight into the relationship between UGGT1 structure and function, integrating enzyme conformational states with client glycoprotein interaction and processing.

Keywords: N-glycosylation; UGGT1; endoplasmic reticulum; glycoproteostasis; protein secretion

DOI: https://doi.org/10.1073/pnas.2621329123