bims-meglyc 2026-06-21 papers

Issue of 2026–06–21
two papers selected by
Silvia Radenkovic, UMC Utrecht

Mol Metab. 2026 Jun 13. pii: S2212-8778(26)00084-0. [Epub ahead of print] 102400

Cross-talk between glycosylation pathways: Mechanistic insights and implications for human diseases.

Glycosylation encompasses a broad spectrum of post-translational modifications (PTMs) that shape protein stability, spatial organization, and function. Traditionally, it is classified into two major categories: complex glycosylation within the secretory pathway - including N-glycosylation, mucin-type O-glycosylation, glycosaminoglycans (GAGs), and glycolipids - which generate structurally stable and long-lived modifications; and O-GlcNAcylation, a highly dynamic modification of nucleocytoplasmic and mitochondrial proteins that rapidly responds to metabolic and environmental cues. While this dichotomous framework has guided our understanding of glycan biology, emerging evidence now reveals that glycosylations are functionally interconnected through shared metabolic substrates, and regulatory circuits. Here, we revisit this classical classification and integrate it into a modern, systems-level view of glycosylation. We highlight the nucleotide sugar UDP-N-acetylglucosamine (UDP-GlcNAc) as a metabolic node reflecting cellular nutrient status and fuelling both complex glycan synthesis and O-GlcNAcylation. UDP-GlcNAc pool fluctuations drive coordinated remodeling across glycosylation pathways, and dysregulation of this hub is associated with diverse human diseases. We discuss how O-GlcNAcylation functions as a supplementary regulatory PTM, modulating glycosylation-related enzymes and proteins through both direct effects on their interactions, stability, localisation and activity, and via broader transcriptional and epigenetic programs, thereby dynamically controlling otherwise stable glycosylation processes. Examples from metabolic, cardiovascular, neurological diseases, cancer and congenital disorders of glycosylation (CDGs) illustrate how perturbations in one glycosylation pathway propagate through the glycosylation network, reshaping cellular identity and disease trajectories. We support a paradigm in which glycosylation operates as an integrated regulatory framework linking metabolism, signaling, and extracellular architecture, providing new perspectives for disease stratification and therapeutic intervention.

Keywords: Glycosylation network; Human diseases; Metabolic regulation; O-GlcNAcylation; UDP-GlcNAc

DOI: https://doi.org/10.1016/j.molmet.2026.102400

Front Neurol. 2026 ;17 1840802

COG5-congenital disorder of glycosylation diagnosed by whole genome sequencing in siblings with unexplained optic atrophy, macular atrophy, and developmental delay: case report.

Katherine Granger, Catherine Do, Catherine Quindipan, Ryan Schmidt, Mark S Borchert, Aaron Nagiel, Melinda Y Chang.

Introduction: COG5-related congenital disorder of glycosylation (COG5-CDG) is a rare autosomal recessive metabolic disorder with variable neurologic and ophthalmologic involvement. We report two siblings presenting with optic atrophy, macular atrophy, and neurodevelopmental delay; these three phenotypic manifestations have not, to our knowledge, been combined together in previously described individuals with COG5-CDG. The genetic disorder was only diagnosed through whole genome sequencing (WGS) after panel-based exome testing was unrevealing.
Clinical findings: Both siblings presented with early-onset severe visual impairment, bilateral optic atrophy, central macular atrophy, sensory nystagmus, and strabismus in the setting of global developmental delay. Additional features included polymicrogyria and hypotonia (Case 1) and microcephaly and autism spectrum disorder (Case 2).
Diagnoses and outcomes: After repeated non-diagnostic inherited retinal gene panels, clinical quad WGS identified compound heterozygous variants in COG5 in both siblings: a paternally inherited pathogenic frameshift variant (c.1415dup) and a maternally inherited deep intronic variant (c.417 + 4779A>G) with high SpliceAI-predicted splicing impact. Visual function has remained relatively stable over 5 years of follow-up.
Conclusion: These cases expand the phenotypic spectrum of COG5-CDG to include concurrent optic nerve and macular involvement with neurodevelopmental impairment and highlight the essential role of WGS in diagnosing complex neuro-ophthalmologic presentations when targeted genetic testing is nondiagnostic.

Keywords: case report; congenital disorders of glycosylation; developmental delay; optic atrophy; retinal dystrophy

DOI: https://doi.org/10.3389/fneur.2026.1840802