bims-meglyc 2025-12-21 papers

Issue of 2025–12–21
four papers selected by
Silvia Radenkovic, UMC Utrecht

Am J Med Genet A. 2025 Dec 15.

DDOST-Congenital Disorder of Glycosylation: Defining the Clinical Spectrum and First Report of a Structural Variant.

Giuseppe Reynolds, Ilaria Carelli, Federico Rondot, Stefania Massuras, Veronica Pagliardini, Vincenza Gragnaniello, Alberto B Burlina, Sara Resciniti, Simona Agata, Davide Colavito, Alessandro Mussa.

Congenital disorders of glycosylation (CDG) are a heterogeneous group of metabolic diseases caused by defects in glycan biosynthesis, predominantly affecting the N-glycosylation pathway. Pathogenic variants in the DDOST gene, encoding a non-catalytic subunit of the oligosaccharyltransferase (OST) complex, underlie an ultra-rare CDG subtype with only three patients reported to date, complicating diagnosis and genotype-phenotype correlations. We describe a female patient with developmental delay, hypotonia, and dysmorphic features. Genetic analyses included chromosomal microarray, FMR1 testing, and trio-based next-generation sequencing with a neurodevelopmental disorder panel. Variants were assessed using ACMG criteria, population databases, segregation, and in silico analysis. We also reviewed published DDOST-CDG cases to compare clinical and molecular findings. Compound heterozygous DDOST variants were identified: (i) a maternally inherited 413-kb deletion encompassing exons 3-11, predicted to abolish gene function, and (ii) a paternally inherited in-frame deletion (p.Lys435del), removing a highly conserved residue in the luminal C-terminal domain. Both were absent from population databases and classified as pathogenic or likely pathogenic, consistent with autosomal recessive inheritance. Metabolic testing confirmed a type I transferrin isoform pattern, supporting a congenital disorder of glycosylation. This report expands the genetic and phenotypic spectrum of DDOST-CDG by describing the first structural variant. Review of published cases highlights hypotonia and motor delay as consistent features, while other traits such as strabismus, feeding difficulties, or hepatic dysfunction appear variable. Our findings underscore the clinical heterogeneity of DDOST-CDG and the complementary role of metabolic and genomic testing.

Keywords: DDOST ; N‐glycosylation pathway; congenital disorders of glycosylation; neurodevelopmental delay

DOI: https://doi.org/10.1002/ajmga.70026

Front Mol Neurosci. 2025 ;18 1674665

Dynamic glycosylation remodeling in neurological disorders.

Dan Xing, Yingxun Gong, Weiyi Xia, Huifang Tu, Limei Yuan, Yiqing Yin, Kaiyuan Wang.

Glycosylation, a crucial post-translational modification, involves the covalent attachment of monosaccharides or oligosaccharides to proteins. This process significantly influences protein stability and function. Within the nervous system, glycosylation regulates key processes including neuronal differentiation, migration, synapse formation, and neurotransmitter release and signaling. Its proper functioning is essential for maintaining neuronal homeostasis and reducing the risk of neurological disorders. Understanding the specific mechanisms by which glycosylation impacts the central nervous system is therefore essential for developing novel therapeutic strategies. This review focuses on the roles of three major glycosylation types-N-glycosylation, O-glycosylation, and O-GlcNAcylation-in the pathogenesis of central nervous system disorders.

Keywords: Alzheimer’s disease; O-GlcNAcylation; glycosylation; neurodegeneration; psychiatry

DOI: https://doi.org/10.3389/fnmol.2025.1674665

J Neuromuscul Dis. 2025 Dec 19. 22143602251405918

Gne deletion in adult mice can cause thrombocytopenia, anemia, myopathy, bleeding, and death.

Patricia Lam, Deborah A Zygmunt, Macey Bennett, Anna Ashbrook, Jessica Hefty, Paul T Martin.

The GNE gene encodes the UDP-GlcNAc-2-epimerase/ManNAc kinase, a bifunctional enzyme required for the synthesis of sialic acid. The mouse Gne gene is essential for embryonic development, but humans with recessive partial loss of function GNE mutations can develop infantile thrombocytopenia, juvenile amyotrophic lateral sclerosis, or adult-onset myopathy (GNE myopathy). We have created inducible Gnelox/lox gene deletion mice to study how loss of Gne in adult mice relates to these disease states. Systemic Gne gene deletion in tamoxifen-treated Rosa-CreERT2/Rosa-CreERT2Gnelox/lox mice caused uniform fatality within 30 days of gene deletion with spontaneous bleeding, thrombocytopenia, and anemia. Skeletal myofiber-specific Gne deletion in tamoxifen-treated HSA-CreERT2/+Gnelox/lox mice had no bleeding and no muscle pathology at 60 or 270 days post-treatment. Intramuscular injection of AAV.MCK.GFP-Cre in Gnelox/lox mice also showed little to no evidence of muscle pathology, while AAV.CMV.GFP-Cre caused extensive muscle damage, reduced muscle force, and changed expression of markers for muscle regeneration, muscle cell senescence, muscle denervation, and muscle atrophy. These data demonstrate that Gne is an essential gene in adult mice that can mimic aspects of human hematologic and muscle diseases caused by GNE mutations, but suggests induction of muscle disease requires loss of gene GNE expression in cell types beyond skeletal myofibers.

Keywords: adeno associated virus; gene therapy; hematology; muscular dystrophy; sialic acid

DOI: https://doi.org/10.1177/22143602251405918

Nat Commun. 2025 Dec 19. 16(1): 11275

Endothelial glycosylation and its emerging role in pulmonary vascular health and disease.

Valeria Nazaire, Kevin Brown Chandler.

Pulmonary vascular disease (PVD) encompasses a group of conditions that impact the blood vessels in the lungs. Endothelial cells, which line blood vessels, bear a conspicuous layer of glycosylated molecules that project into the vascular lumen. Recent findings support a role for endothelial cell glycosylation in the development and progression of PVD. However, glycosylation remains a critically understudied aspect of pulmonary vascular health and disease. Here, we provide an overview of the functional role of endothelial cell glycosylation, present evidence of the involvement of glycosylation in PVD, and outline gaps in knowledge regarding the role of glycosylation within the pulmonary vasculature, to provide a foundation for future research efforts focused on advancing glycosylation pathway-targeted treatments for pulmonary vascular disease.

DOI: https://doi.org/10.1038/s41467-025-66169-x