bims-meglyc 2026-08-02 papers

bims-meglyc

Biomed News

on Metabolic disorders affecting glycosylation

Issue of 2026–08–02
eight papers selected by
Silvia Radenkovic, UMC Utrecht

B4GALT1-related congenital disorder of glycosylation mimicking Ehlers-Danlos syndrome: a child with multisystem involvement and nephrotic syndrome.
Diagnosis of Congenital Disorders of Glycosylation Type II Subtypes Through Comprehensive N-Glycan Profiling by Mass Spectrometry.
Novel ALG13 Variants and an Expanded Neurodevelopmental Spectrum: Genotype-Phenotype Correlations.
Congenital Disorders of Glycosphingolipid Biosynthesis: Ultrarare Severe Syndromes or Relatively Frequent Mild Neurocognitive Illnesses?
Bis(monoacylglycero)phosphate (BMP) as a circulating biomarker of lysosomal dysfunction in GNE myopathy.
Hexosamine Pathway Disruption by GFPT1 Loss Drives Coordinated Defects in Glycosylation, Autophagy, and Trafficking.
COG7 links Golgi integrity to stress signaling and senescence.
Mechanisms of Quality Control in GPI-Anchored Proteins: The Central Role of the Lipid Anchor.

Clin Exp Pediatr. 2026 Jul 20.

B4GALT1-related congenital disorder of glycosylation mimicking Ehlers-Danlos syndrome: a child with multisystem involvement and nephrotic syndrome.

Marifat Ganieva, Muqaddas Boltaboeva, Umida Ganiyeva, Oksana Efimenko, Abdulhamid Haydarov, Sherzod Toshboyev.

DOI: https://doi.org/10.3345/cep.2026.00563
Int J Mol Sci. 2026 Jul 15. pii: 6309. [Epub ahead of print]27(14):

Diagnosis of Congenital Disorders of Glycosylation Type II Subtypes Through Comprehensive N-Glycan Profiling by Mass Spectrometry.

Alan R Mól, Nilza do C Fontes, Savana C L Santos, Cynthia Costa E Silva, Gerson da S Carvalho, Bruno J C B Lima, Walquíria D de Mello, Daniel R de Carvalho, Eder A Barbosa, Dirk J Lefeber, Juliana F Mazzeu, Jaime M Brum, Guilherme D Brand.

  Congenital disorders of glycosylation (CDG) are a group of inherited metabolic diseases rapidly growing due to the discovery of new subtypes. As with many genetic conditions, their diagnosis can be challenging, impairing proper patient care and causing additional suffering to patients and their families. We have developed an N-glycomics strategy that can provide insightful information towards diagnosing CDG type II (CDG-II). N-glycans released from the plasma of healthy individuals were labeled with deuterated iodomethane, mixed with samples from known or suspected CDG-II individuals, which were derivatized with standard iodomethane, and analyzed by liquid chromatography-mass spectrometry. After identification, relative quantification of 65 glycans was performed, revealing considerable alterations in the N-glycome of several patients. Notably, reduced fucosylation was observed in patients with FUT8-CDG and SLC35C1-CDG. Additionally, individuals with mutations in the MAN1B1 gene exhibited increased amounts of hybrid and oligomannosidic structures, whereas patients with the Golgi homeostasis disorders COG1-CDG and ATP6V0A2-CDG presented marked increases in hypogalactosylated and hyposialylated structures. Multivariate statistical analysis indicated two undiagnosed patients with alterations similar to ATP6V0A2-CDG patients and another two with a profile similar to MAN1B1-CDG patients. Genetic sequencing (targeted gene panel or whole exome sequencing) of these undiagnosed patients revealed variants in the corresponding genes, confirming the diagnosis obtained from the N-glycomics analysis. Our results demonstrate how the analysis of total plasma N-glycans can be used to identify metabolic disorders and diagnose conditions based on their molecular effects on the glycoproteome.

Keywords:  congenital disorders of glycosylation; glycomics; inherited metabolic diseases; mass spectrometry; stable isotopic labeling

DOI:  https://doi.org/10.3390/ijms27146309
Hum Mutat. 2026 ;2026 6800099

Novel ALG13 Variants and an Expanded Neurodevelopmental Spectrum: Genotype-Phenotype Correlations.

Song Su, Wandong Hu, Ying Ren, Tong Zhang, Chunmei Yu, Hongwei Zhang.

   Background: The ALG13 gene is implicated in congenital disorders of glycosylation (CDG) and developmental and epileptic encephalopathy (DEE), yet genotype-phenotype correlations remain incompletely understood.
Methods: Whole-exome sequencing (WES) was performed in unrelated families, and we systematically reviewed existing patient data on ALG13 variants and investigated the expression patterns of ALG13 using organoid models.
Results: This study reports five patients with ALG13 variants, including two novel variants. Four patients presented with epilepsy accompanied by neurodevelopmental impairment, including infantile epileptic spasms syndrome (IESS) and drug-resistant epilepsy, whereas one patient showed developmental delay without seizures. Further analysis revealed that variants identified in patients with isolated developmental delay were primarily located outside the key glycosylation functional domain. Statistical analysis of patients with epileptic encephalopathy showed that infantile-onset seizures were the predominant feature, with most cases being refractory to treatment. Additionally, in organoids, the highest ALG13 expression was observed at 1 month in ectodermal-derived neurons (EN). At 5 months, peak expression shifted to deep-layer cortical neurons (EN-CTX-Deep).
Conclusions: ALG13 variants are associated with a broad phenotypic spectrum ranging from DEE to neurodevelopmental impairment without seizures. Our findings support a possible domain-related genotype-phenotype association and provide additional developmental context for the role of ALG13 in neurodevelopmental disorders. Further functional studies are required to clarify the pathogenic mechanisms of different ALG13 variants.

Keywords:  ALG13 gene; congenital disorders of glycosylation; developmental and epileptic encephalopathy; genotype–phenotype; organoids

DOI:  https://doi.org/10.1155/humu/6800099
Biomedicines. 2026 Jul 03. pii: 1506. [Epub ahead of print]14(7):

Congenital Disorders of Glycosphingolipid Biosynthesis: Ultrarare Severe Syndromes or Relatively Frequent Mild Neurocognitive Illnesses?

Linda Montavoci, Michele Dei Cas, Sara Penati, Marco Trinchera.

  Glycosphingolipids (GSLs) are glycoconjugates in which a short and heterogeneous saccharide chain is attached to a lipid moiety called ceramide. Based on their sugar backbone, mammalian GSLs are primarily grouped into the ganglio-, lacto-/neolacto-, and globo-series. Sialic acid-containing GSLs are known as gangliosides. Complex ganglio-series gangliosides are particularly abundant in the brain, whereas simple ganglio-series gangliosides, as well as those belonging to other series or neutral GSLs, are less abundant and typical of non-neural tissues. Congenital disorders in the biosynthesis of the lipid moiety of sphingolipids (SLs) result from defects in enzymes and proteins involved in ceramide biosynthesis and transport. Congenital disorders in the biosynthesis of the sugar chain of GSLs specifically affect ganglio-series ganglioside biosynthesis and are caused by pathogenic variants in GM3 synthase (ST3GAL5) or GM2/GD2/asialo-GM2 synthase (B4GALNT1). Defective variants of the sialyltransferase ST3GAL3 and the galactosyltransferase B4GALT5 have been reported and proposed to impair GSL biosynthesis. The occurrence of these syndromes has provided new insights into the physiological and pathological roles of GSLs. Most of these disorders are associated with completely inactive enzyme variants, leading to severe neurological syndromes. Only a few cases highlighted variants that retained partial activity, resulting in milder phenotypes, which included non-syndromic intellectual disability. It is therefore conceivable that many undiagnosed patients, with mild neurological symptoms, may carry variants retaining residual enzyme activity, insufficient to ensure normal levels of brain GSLs. The purpose of this article is to encourage clinicians to look for additional GLS hereditary disorders associated with a milder phenotype. We also hope to boost future investigations by highlighting the most critical issues emerging from recent literature on SL and GSL biosynthesis and their related defects.

Keywords:  ceramides; congenital disorders of glycosylation; epilepsy; gangliosides; intellectual disability

DOI:  https://doi.org/10.3390/biomedicines14071506
Clin Chim Acta. 2026 Jul 25. pii: S0009-8981(26)00426-2. [Epub ahead of print]593 121244

Bis(monoacylglycero)phosphate (BMP) as a circulating biomarker of lysosomal dysfunction in GNE myopathy.

Cristina Manis, Fabrizio Pertusati, James Morewood, Andreas Roos, Felix Kleefeld, Michela Onali, Oksana Pogoryelova, Alexa Derksen, Sally Spendiff, Hanns Lochmuller, Paula Videira, Luigi Atzori, Pierluigi Caboni.

  GNE myopathy (GNEM) is a rare neuromuscular disorder caused by pathogenic variants in the GNE gene and traditionally associated with impaired sialic acid biosynthesis. In a previous untargeted lipidomic study, we identified a lipid feature significantly enriched in the serum of patients with GNE myopathy compared with healthy controls. In the present work, we aimed to determine the structural identity of this disease-associated feature and to establish a robust analytical strategy for its quantitative assessment. Analysis of the mass spectrometric data pointed to bis(monoacylglycero)phosphate 18:1_18:1 or BMP (18:1_18:1) as a plausible candidate, based on the consistency of the nominal mass and fragmentation pattern with this lipid class. In the present work, we therefore aimed to determine the structural identity of this disease-associated feature and to establish a robust analytical strategy for quantitative assessment. We therefore performed the chemical synthesis of BMP (18:1_18:1) and, based on its MS/MS fragmentation pattern, developed a selective tandem mass spectrometry method for its quantification. Levels of BMP (18:1_18:1) were measured in serum samples from patients with GNE myopathy, healthy controls, and patients with myotonic dystrophy type 2 (DM2) as a disease comparison cohort. BMP levels were significantly increased in the serum of patients with GNE myopathy compared with both healthy controls and DM2 patients. Together, these findings define a previously unrecognized circulating lipid alteration in GNE myopathy and provide new insight into disease-associated lipid dysregulation.

Keywords:  BMP; GNEM, Nonaka myopathy; HIBM; Lipidomics; Lysosomal alteration

DOI:  https://doi.org/10.1016/j.cca.2026.121244
Biomolecules. 2026 Jun 30. pii: 966. [Epub ahead of print]16(7):

Hexosamine Pathway Disruption by GFPT1 Loss Drives Coordinated Defects in Glycosylation, Autophagy, and Trafficking.

Stephen H Holland, Ricardo Carmona-Martinez, Andreas Hentschel, Alexa Derksen, Kaela O'Connor, Daniel O'Neil, Kelly Ho, Stephen D Baird, Andreas Roos, Sally Spendiff, Hanns Lochmüller.

  Glutamine-Fructose-6-Phosphate Transaminase 1 (GFPT1), the rate-limiting enzyme of the hexosamine biosynthetic pathway (HBP), provides the UDP-N-acetylglucosamine (UDP-GlcNAc) required for protein glycosylation. Biallelic mutations in GFPT1 cause congenital myasthenic syndromes (GFPT1-CMS), yet the molecular mechanisms linking impaired glycosylation to skeletal muscle dysfunction remain incompletely understood. Here, we combine cellular models of inducible Gfpt1 knockdown and a skeletal muscle-specific Gfpt1 knockout mouse (Gfpt1Tm1d/Tm1d) with whole-cell proteomics, immunoblot studies and secretomics to define glycosylation-dependent defects in intracellular trafficking, ER stress signaling and autophagy. Global proteomic profiling of Gfpt1-deficient myoblasts revealed marked downregulation of protein trafficking pathways and impaired secretion of key muscle cargo proteins, including serglycin (Srgn). Loss of GFPT1 reduced both high-molecular-weight glycosylated serglycin and its core protein, accompanied by intracellular retention and decreased secretion. These trafficking defects coincide with robust activation of the unfolded protein response (UPR), evidenced by increased Xbp1 expression and accumulation of spliced Xbp1s across pharmacologic, cellular, and mouse models of GFPT1 deficiency. Converging evidence from proteomics, immunoblotting, and immunofluorescence demonstrated impaired autophagy, including increased LC3-II accumulation, elevated p62/Sqstm1 levels, and enhanced p62-positive puncta in both Gfpt1-deficient C2C12 myoblasts and skeletal muscle. Soluble/insoluble fractionation further confirmed p62 accumulation, indicating defective autophagic flux and buildup of aggregated cargo. Together, these findings identify a glycosylation-dependent failure in protein trafficking that triggers ER stress, UPR activation, and autophagy impairment in Gfpt1-deficient skeletal muscle. This mechanistic cascade provides a unifying explanation for muscle pathology in GFPT1-CMS and suggests that restoring glycosylation or improving proteostasis may represent viable therapeutic approaches.

Keywords:  GFPT1; autophagy; congenital myasthenic syndrome; glycosylation; trafficking

DOI:  https://doi.org/10.3390/biom16070966
Plant J. 2026 Aug;127(3): e71077

COG7 links Golgi integrity to stress signaling and senescence.

María Fernanda Gómez-Méndez, Yahir Oseguera, Genesis Oseguera, Jingzhe Guo, Rachel Wu, Tyler Inskeep, Jinzheng Wang, Heeseung Choi, Katayoon Dehesh.

  The mechanisms linking Golgi function to stress adaptation and senescence remain poorly understood. Here, we identify the conserved oligomeric Golgi (COG) subunit COG7 as a non-redundant determinant of Golgi integrity and stress adaptation in Arabidopsis thaliana. Functional disruption of COG7 reduces Golgi size, enhances Rapid Stress Response Element (RSRE)-dependent stress signaling, and accelerates dark-induced senescence. Complementation analyses reveal functional specialization within the COG complex, as only COG3, COG5, and COG6 partially restore stress signaling and senescence phenotypes. At the molecular level, cog7 exhibits altered glycosylation, increased ubiquitination, and elevated autophagy. However, disruption of glycosylation pathways or dark-induced candidate glycosyltransferases does not affect RSRE activation, proteostasis-associated responses, or senescence progression, indicating that glycosylation changes are downstream consequences rather than drivers of the stress phenotype. Similarly, CAMTA3-dependent RSRE activation is genetically separable from senescence and proteostasis pathways. Together, these findings show that Golgi dysfunction generates multiple parallel outputs rather than a single linear stress pathway and establish COG7 as a central regulator linking Golgi integrity to stress signaling, proteostasis, and senescence during dark-induced stress.

Keywords:  COG complex; Golgi apparatus; autophagy; proteostasis; senescence; stress signaling

DOI:  https://doi.org/10.1111/tpj.71077
Int J Mol Sci. 2026 Jul 16. pii: 6316. [Epub ahead of print]27(14):

Mechanisms of Quality Control in GPI-Anchored Proteins: The Central Role of the Lipid Anchor.

Leticia Lemus, Prasanna Satpute-Krishnan, Veit Goder.

  Glycosylphosphatidylinositol-anchored proteins (GPI-APs) are a distinct class of eukaryotic cell-surface proteins characterized by a glycolipid anchor at their C-terminus. They display unique biophysical properties and play important roles in human diseases, including transmissible spongiform encephalopathies (TSEs), malaria, sleeping sickness, and rare disorders collectively termed inherited GPI deficiency (IGD). Because of their broad clinical relevance, GPI-APs have become a major focus of research, including their intracellular quality control (QC). Studies in diverse model organisms have revealed striking interspecies differences in GPI-AP QC pathways and notable distinctions from QC mechanisms and the degradation of misfolded species governing other secretory proteins. In this review, we summarize recent advances in the understanding of these cellular processes and propose that the observed variations in QC reflect distinct cellular strategies that balance protein QC with membrane homeostasis across evolutionary contexts.

Keywords:  GPI anchor remodeling; RESET; endoplasmic reticulum (ER); glycosylphosphatidylinositol (GPI) anchor; microautophagy; post-ER quality control; vacuole/lysosome

DOI:  https://doi.org/10.3390/ijms27146316