bims-meglyc 2025-03-30 papers

Issue of 2025–03–30
four papers selected by
Silvia Radenkovic, UMC Utrecht

Handb Exp Pharmacol. 2025 Mar 22.

Diagnostic and Therapeutic Approaches in Congenital Disorders of Glycosylation.

Alexandre Raynor, Élodie Lebredonchel, François Foulquier, François Fenaille, Arnaud Bruneel.

Congenital disorders of glycosylation (CDG) constitute an increasing group of inborn metabolic disorders, with more than 170 described diseases to date. A disturbed glycosylation process characterizes them, with molecular defects localized in distinct cell compartments. In CDG, N-glycosylation, O-glycosylation, glycosylation of lipids (including phosphatidylinositol) as well as the glycosaminoglycan synthesis can be affected. Owing to the importance of glycosylation for the function of concerned proteins and lipids, glycosylation defects have diverse clinical consequences. CDG affected individuals often present with a non-specific multivisceral syndrome including neurological involvement, intellectual disability, dysmorphia, and hepatopathy. As CDG are rare diseases frequently lacking distinctive symptoms, biochemical and genetic testing bear important and complementary diagnostic roles.After an introduction on glycosylation and CDG, we review current biomarkers and analytical techniques in the field. Furthermore, we illustrate their interests in the follow-up of proven therapeutic approaches including D-mannose in MPI-CDG, D-galactose in PGM1-CDG, and manganese (MnSO4) in TMEM165-CDG.

Keywords: Apolipoprotein C-III; Bikunin; CDG; Galactose; Glycosylation; MPI-CDG; Manganese; Mannose; PGM1-CDG; TMEM165-CDG; Transferrin

DOI: https://doi.org/10.1007/164_2025_745

Mol Genet Metab. 2025 Mar 19. pii: S1096-7192(25)00078-2. [Epub ahead of print]145(1): 109087

Goal attainment in PMM2-CDG: A new approach measuring meaningful clinical outcomes.

Sanne Verberkmoes, Gina L Mazza, Andrew C Edmondson, Fernando Scaglia, Seishu Horikoshi, Bryce Kuschel, Mirian C H Janssen, Jehan Mousa, Austin Larson, Rameen Shah, Georgia McDonald, Kyriaki Sarafoglou, Gerard Berry, Tamas Kozicz, Christina Lam, Eva Morava.

Patient-centered outcomes, including patient-reported outcomes (PROs), are increasingly important in healthcare and research, though their use in rare diseases remains limited. In disorders with significant phenotypic variation, selecting appropriate outcome measures is crucial to ensuring the relevance of clinical trials for the patient population. Phosphomannomutase 2-CDG (PMM2-CDG) involves a complex genotype-phenotype relationship, making it challenging to predict clinical outcomes and select reliable measures for clinical trials. Caused by biallelic pathogenic variants in the PMM2, PMM2-CDG displays highly variable clinical severity, underscoring the need for personalized outcome measures. One such so far unexplored, individualized approach is Goal Attainment Scaling (GAS), which allows patients to set and track personal goals over time. We evaluated 93 PMM2-CDG patients enrolled in the Frontiers in Congenital Disorders of Glycosylation Consortium (FCDGC) Natural History study, classifying patient goals using the International Classification of Functioning, Disability, and Health (ICF) model, and assessing goal achievement prospectively. We also analyzed potential associations between GAS and factors such as age, sex, genetic background, and disease severity measured by the Nijmegen Progression CDG Rating Scale (NPCRS). The most common goals set by patients were related to mobility (31.5 %) and communication (26.8 %), with additional goals focused on body function (22.8 %) and independence (18.8 %). Of the 68 patients with follow-up data, 23.5 % showed no improvement in their goals, while 20.6 % improved in all three personal goals. Patients with pathogenic variants affecting the PMM2 dimerization domain had lower GAS improvement scores (M = 1.3 [SD = 1.1]) compared to those without such variants (M = 2.2 [SD = 1.7], p = 0.03). There was no significant correlation between NPCRS score changes and GAS improvement (r = -0.18, p = 0.19). GAS is a valuable additional outcome measure that ensures clinical improvements are meaningful for patients and their representatives, helping to assess individual goals and overall wellbeing.

Keywords: Genotype-phenotype, congenital disorders of glycosylation; Goal attainment scaling; Patient reported outcome; Phosphomannomutase

DOI: https://doi.org/10.1016/j.ymgme.2025.109087

JCI Insight. 2025 Mar 25. pii: e173484. [Epub ahead of print]

SEC24C deficiency causes trafficking and glycosylation abnormalities in an epileptic encephalopathy with cataracts and dyserythropoeisis.

As a major component of intracellular trafficking, the coat protein complex II (COPII) is indispensable for cellular function during embryonic development and throughout life. The four SEC24 proteins (A-D) are essential COPII components involved in cargo selection and packaging. A human disorder corresponding to alterations of SEC24 function is currently only known for SEC24D. Here, we report that biallelic loss of SEC24C leads to a syndrome characterized by primary microcephaly, brain anomalies, epilepsy, hearing loss, liver dysfunction, anemia, and cataracts in an extended consanguineous family with four affected individuals. We show that knockout of sec24C in zebrafish recapitulates important aspects of the human phenotype. SEC24C-deficient fibroblasts display alterations in the expression of several COPII components as well as impaired anterograde trafficking to the Golgi, indicating a severe impact on COPII function. Transcriptome analysis revealed that SEC24C deficiency also impacts the proteasome and autophagy pathways. Moreover, a shift in the N-glycosylation pattern and deregulation of the N-glycosylation pathway suggest a possible secondary alteration of protein glycosylation, linking the described disorder with the congenital disorders of glycosylation.

Keywords: Epilepsy; Genetics; Glycobiology; Neuroscience; Protein traffic

DOI: https://doi.org/10.1172/jci.insight.173484

Genome Biol. 2025 Mar 24. 26(1): 69

Functional genomic profiling of O-GlcNAc reveals its context-specific interplay with RNA polymerase II.

Sofia Rucli, Nicolas Descostes, Yulia Ermakova, Urvashi Chitnavis, Jeanne Couturier, Ana Boskovic, Matthieu Boulard.

BACKGROUND: How reversible glycosylation of DNA-bound proteins acts on transcription remains scarcely understood. O-linked β-N-acetylglucosamine (O-GlcNAc) is the only known form of glycosylation modifying nuclear proteins, including RNA polymerase II (RNA Pol II) and many transcription factors. Yet, the regulatory function of the O-GlcNAc modification in mammalian chromatin remains unclear.
RESULTS: Here, we combine genome-wide profiling of O-GlcNAc-modified proteins with perturbations of intracellular glycosylation, RNA Pol II-degron, and super-resolution microscopy. Genomic profiling of O-GlcNAc-modified proteins shows a non-random distribution across the genome, with high densities in heterochromatin regions as well as on actively transcribed gene promoters. Large-scale intersection of the O-GlcNAc signal at promoters with public ChIP-seq datasets identifies a high overlap with RNA Pol II and specific cofactors. Knockdown of O-GlcNAc Transferase (Ogt) shows that most direct target genes are downregulated, supporting a global positive role of O-GlcNAc on the transcription of cellular genes. Rapid degradation of RNA Pol II results in the decrease of the O-GlcNAc levels at promoters encoding transcription factors and DNA modifying enzymes. RNA Pol II depletion also unexpectedly causes an increase of O-GlcNAc levels at a set of promoters encoding for the transcription machinery.
CONCLUSIONS: This study provides a deconvoluted genomic profiling of O-GlcNAc-modified proteins in murine and human cells. Perturbations of O-GlcNAc or RNA Pol II uncover a context-specific reciprocal functional interplay between the transcription machinery and the O-GlcNAc modification.

Keywords: CUT&RUN; ChIP-seq; ChIP‐Atlas; Degron; Glycosylation; O-GlcNAc; O-linked β-N-acetylglucosamine; OGT; Promoter; RNA polymerase II; RNA-seq; Transcription

DOI: https://doi.org/10.1186/s13059-025-03537-2