bims-meglyc 2025-08-03 papers

Issue of 2025–08–03
four papers selected by
Silvia Radenkovic, UMC Utrecht

Mol Genet Metab. 2025 Jul 19. pii: S1096-7192(25)00186-6. [Epub ahead of print]146(1-2): 109195

Predicting disease-overarching therapeutic approaches for congenital disorders of glycosylation using multi-OMICS.

I J J Muffels, R Budhraja, R Shah, S Radenkovic, E Morava, T Kozicz.

BACKGROUND: Congenital Disorders of Glycosylation (CDG) are a rapidly expanding group of inherited metabolic diseases caused by defects in glycosylation. Although over 190 genetic defects have been identified, effective treatments remain available for only a few. We hypothesized that integrative analysis of multi-omics datasets from individuals with various CDG could uncover common molecular signatures and highlight shared therapeutic targets.
METHODS: We compiled all publicly available RNA sequencing, proteomics and glycoproteomics datasets from patients with PMM2-CDG, ALG1-CDG, SRD5A3-CDG, NGLY1-CDDG, ALG13-CDG and PGM1-CDG, spanning different tissues, including induced cardiomyocytes, human cortical organoids, fibroblasts, and lymphoblasts. Differential expression and glycosylation analyses were performed, followed by Gene Set Enrichment Analysis (GSEA) to identify commonly dysregulated pathways. We then applied the EMUDRA drug prediction algorithm to prioritize candidate compounds capable of reversing these shared molecular signatures.
RESULTS: We identified four glycoproteins with consistent differential glycosylation across all eight glycoproteomics datasets. Six glycosylation sites and glycan structures were recurrently altered across CDG and showed partial correction with treatment. Pathway analysis revealed shared disruptions in autophagy, vesicle trafficking, and mitochondrial function. EMUDRA predicted several repurposable drug classes, including muscle relaxants, antioxidants, beta-adrenergic agonists, antibiotics, and NSAIDs, that could reverse key pathway abnormalities, particularly those involving autophagy and N-glycosylation.
CONCLUSION: Most dysregulated pathways were shared across CDG, suggesting the potential for common therapeutic strategies. Several candidate drugs targeting these shared abnormalities emerged from integrative analysis and warrant validation in future in vitro studies.

Keywords: CDG; Congenital disorders of glycosylation; Drug prediction; Drug repositioning; Drug repurposing; Genetic disease; Genetic disorder; Inherited disorder of metabolism; Metabolic disease; Proteomics; Transcriptomics

DOI: https://doi.org/10.1016/j.ymgme.2025.109195

Mol Genet Metab. 2025 Jul 13. pii: S1096-7192(25)00179-9. [Epub ahead of print]146(1-2): 109188

Incidence and prevalence of phosphomannomutase 2-congenital disorder of glycosylation: Past, present, and future.

Andrew C Edmondson, Tomáš Honzík, Christina Lam, Katrin Õunap, Peter McWilliams, Eva Morava.

Phosphomannomutase 2-congenital disorder of glycosylation (PMM2-CDG) accounts for about 60 % of all CDGs and is caused by pathogenic variants of the gene encoding PMM2, which catalyzes an essential early step in N-linked glycosylation. Efforts to derive an accurate prevalence estimate for this often life-threatening disorder, for which there are currently no approved therapies, are hampered by the wide spectrum of clinical manifestations, the rarity of the disease, and the lack of a central global patient registry. Here, we calculated new estimates of PMM2-CDG incidence and prevalence in North America and Europe based on the frequency of disease-causing alleles using the Hardy-Weinberg equation. Allele frequencies were obtained from the Genome Aggregation Database (gnomAD v4.0) and the likelihood of specific allele combinations resulting in a live birth was adjusted based on the occurrence of genotypes in patient datasets and the expected consequences for protein function. New incidence and prevalence estimates were then calculated in the context of historical ethnicity and birth data from national statistical databases, combined with estimated patient mortality rates. The calculated new incidence estimate was 1 in 33,576 for North America and Europe combined (1 in 40,375 and 29,043, respectively), which predicts an average of 303 live births per year for both regions combined since 1980. The new prevalence estimate was 1 in 63,694 (1 in 76,183 and 57,022 in North America and Europe, respectively), which translates to a total of 14,154 patients living with PMM2-CDG in North America and Europe. Notably, this prevalence is more than 5-fold higher than the current estimate of 2447 diagnosed cases combined, and 10-fold higher than the worldwide prevalence most frequently quoted in the literature. These striking differences highlight the underdiagnosis of the disease and the critical need for improved diagnostic and therapeutic strategies for PMM2-CDG.

Keywords: Glycosylation; Hardy–Weinberg; Incidence; PMM2-CDG; Phosphomannomutase 2; Prevalence

DOI: https://doi.org/10.1016/j.ymgme.2025.109188

Genes (Basel). 2025 Jul 03. pii: 800. [Epub ahead of print]16(7):

Genetic Diseases of Fucosylation: Insights from Model Organisms.

Muhammad T Ameen, Curtis R French.

Fucosylation plays a fundamental role in maintaining cellular functions and biological processes across all animals. As a form of glycosylation, it involves the biochemical addition of fucose, a six-carbon monosaccharide, to biological molecules like lipids, proteins, and glycan chains. This modification is essential for optimizing cellular interactions required for receptor-ligand binding, cell adhesion, immune responses, and development. Disruptions in cellular fucose synthesis or in the mechanisms enabling its transfer to other molecules have been linked to human disease. Inherited defects in the fucosylation pathway are rare, with about thirty patients described. Through genome-wide association studies (GWAS), variants in fucosylation pathway genes have been associated with complex diseases such as glaucoma and stroke, and somatic mutations are often found in cancers. Recent studies have applied targeted genetic animal models to elucidate the mechanisms through which disruptions in fucosylation contribute to disease pathogenesis and progression. Key focus areas include GDP-fucose synthesis through de novo or salvage pathways, GDP-fucose transport into the Golgi and endoplasmic reticulum (ER), and its transfer by fucosyltransferases (FUTs) or protein O-fucosyltransferases (POFUTs) onto acceptor molecules. Loss or gain of function fucosylation gene mutations in animal models such as mice, zebrafish, and invertebrates have provided insights into some fucosylation disease pathogenesis. This review aims to bring together these findings, summarizing key insights from existing animal studies to possibly infer fucosylation disease mechanisms in humans.

Keywords: C. elegans; CDG IIC; LADII; drosophila; epilepsy; fucosylation; glaucoma; leukocytosis; mouse; zebrafish

DOI: https://doi.org/10.3390/genes16070800

J Hum Genet. 2025 Jul 29.

NGLY1 deficiency - clinical features and therapeutic strategy.

Haruhiko Fujihria, Hiroto Hirayama, Tadashi Suzuki.

NGLY1 deficiency is a rare autosomal recessive genetic disorder caused by biallelic mutations of the human NGLY1 gene. NGLY1 encodes the cytosolic peptide:N-glycanase (PNGase; NGLY1 in mammals), which plays essential roles in cytosolic glycan degradation (non-lysosomal glycan degradation), the endoplasmic reticulum (ER)-associated degradation (ERAD) of misfolded proteins, and the complete activation of the transcription factor nuclear factor erythroid 2-like 1 (NEF2L1). NFE2L1 contributes to the regulation of the expression of proteasome subunits and oxidative stress responses. Patients with NGLY1 deficiency exhibit multisystemic clinical features, including global developmental delay, peripheral neuropathy, hypolacrima or alacrima, and the transient elevation of liver transaminases. To date, more than 100 individuals with NGLY1 deficiency and over 70 distinct pathogenic mutations in the NGLY1 gene have been reported. There is currently no approved therapy for this disorder. Moreover, the underlying pathogenic mechanism, including the correlation between patients' symptoms and mutant alleles, remains poorly understood. In this review, we summarize the most frequently reported NGLY1 mutations and their associated clinical features. We also present an overview of the current therapeutic strategy for NGLY1 deficiency.

DOI: https://doi.org/10.1038/s10038-025-01376-4