bims-meglyc 2025-10-12 papers

bims-meglyc

Biomed News

on Metabolic disorders affecting glycosylation

Issue of 2025–10–12
eight papers selected by
Silvia Radenkovic, UMC Utrecht

Exploring Secondary Biotinidase Deficiency and Biotin Supplementation in PMM2-CDG.
The Importance of N- and O-Glycosylation of Brain Cell Surface Glycoproteins.
Immunopathology in PMM2-CDG: Defective glycosylation impact in the TNFα -TNFR1 signalling pathway.
A Treatable Cause of Seizures and Hyperphosphatasia: Patients with PGAP2 and PGAP3 Mutations.
Homozygous PGAP2 Mutation Causes Hyperphosphatasia with Mental Retardation Syndrome-3: Genetic and Clinical Evaluation of the Ultra-Rare Inherited Glycosylphosphatidylinositol Biosynthesis Defect.
A pyrophosphatase that regulates lipid precursors of N-glycosylation.
Asparagine-linked glycosylation protein 1 (ALG1) promotes aggressive phenotypes of lung adenocarcinoma cells, A549, via modulating N-linked glycosylation and ER-Stress.
SLC26A1 directs sulfate homeostasis in health and disease.

Neuropediatrics. 2025 Oct 06.

Exploring Secondary Biotinidase Deficiency and Biotin Supplementation in PMM2-CDG.

Nastassja Himmelreich, Sven F Garbade, Jürgen G Okun, Simone Hengst, Virginia Geiger, Rita Barone, Saskia B Wortmann, Christian Thiel.

The congenital disorders of glycosylation (CDG) encompass >190 multiorgan disorders with predominantly neurodevelopmental phenotypes with no causative treatment available. The glycoprotein biotinidase (BTD) provides biotin, an essential cofactor for carboxylases in ubiquitous metabolic pathways. Individuals with (partial) BTD deficiency (BTDD) and CDG patients show overlapping phenotypes like movement disorders, seizures, and neurodevelopmental issues. Biotin is a water-soluble, inexpensive, and safe food supplement. Patients with primary BTDD respond well to oral biotin supplement. We here explore secondary BTDD and the effect of biotin supplementation in PMM2-CDG in an initial open-label study.BTD activity in dried blood spots from 29 individuals with PMM2-CDG indicated a mean reduction to 27% (range: 23.0-40.5%) at group level. Patients (mean: 19.6 ± 11.9 years) were supplemented with 10 mg biotin daily for 12 months. The parents/caretaker reported positive responses in 62 to 69% of patients across seven (performance, social, at home, self-control, self-care, leisure, health) of the nine categories covered by the Adaptive Behavior Assessment System-II (ABAS-II) questionnaires. The reported positive effect of biotin supplementation differed between age groups, ranging from 54% (16-43 years) via 62% (2-5 years) to 80% (6-13 years). Its effect was reported to be the highest in the moderate to severely affected patient subgroups, with significant improvements in home functioning, health, performance, leisure, self-control. No adverse effects were reported.Given the absence of other treatments, the supportive effect of Biotin in PMM2-CDG deserves further exploration.

DOI: https://doi.org/10.1055/a-2708-3016
Glycobiology. 2025 Oct 10. pii: cwaf054. [Epub ahead of print]

The Importance of N- and O-Glycosylation of Brain Cell Surface Glycoproteins.

Maxence Noel, Yumi M Zürcher, Ea K C Tulin, Richard D Cummings.

  The mammalian brain is unique in its cell types, mainly neurons and glial cells, and the glycoproteins expressed by these cells. Two of the most abundant types of modifications of cell surface glycoproteins are N-glycans linked to Asn residues and O-glycans linked via GalNAc to Ser/Thr residues. Recent studies focused on glycoproteomics, glycomics and glycan localization in the brain reveal major differences in these protein modifications compared to other organs. Deficiencies in glycosylation are associated with the development of multiple brain disorders such as congenital disorders of glycosylation (CDG) that include brain structural abnormalities, epilepsy and seizures to more common disorders including schizophrenia and Alzheimer's disease. Here we summarize recent advances in the growing field of neuro-glycobiology and highlight key points that could be used as primer for future studies.

Keywords:  N- and O-glycosylation; brain development; brain disorders; glycoproteins; secretory pathway

DOI:  https://doi.org/10.1093/glycob/cwaf054
Front Immunol. 2025 ;16 1655354

Immunopathology in PMM2-CDG: Defective glycosylation impact in the TNFα -TNFR1 signalling pathway.

Carlota Pascoal, Pedro Granjo, Rebeka Kodríková, Marta Falcão, Ana C Santos, Inês Teodoro, Zuzana Pakanová, Marek Nemčovič, Jan Mucha, Margarida Castro-Caldas, Ana R Grosso, Vanessa Dos Reis Ferreira, Paula A Videira.

   Introduction: Glycosylation is a post-translational modification that plays a crucial role in immune system activity. Phosphomannomutase 2-Congenital Disorder of Glycosylation (PMM2-CDG) is a rare genetic disease affecting glycosylation with a multi-systemic impact. PMM2-CDG patients commonly show immune disfunction and elevated pro-inflammatory cytokine levels that may link to other symptoms. However, the underlying immune mechanisms remain unclear. Given Tumour Necrosis Factor (TNF)'s key role in inflammation, this study proposes that defective glycosylation of its receptors disrupts intracellular signalling, leading to changes in the immune response of PMM2-CDG patients.
Methods: To address this, we applied an integrative approach, combining transcriptomics, glycomics, and immune-related assays to investigate the impact of TNF-a stimulation via TNF receptor 1 (TNFR1) in a cohort of PMM2-CDG patients' skin fibroblasts.
Results: Our results reveal a multifaceted disruption of TNF-a signalling in PMM2-CDG fibroblasts. We observed structural abnormalities in TNFR1, including altered receptor shedding. PMM2-CDG cells also showed an altered N-glycosylation profile, affecting particularly, high mannose N-glycans. At transcriptional level, PMM2-CDG cells, especially those bearing the R141H heterozygous variant, exhibited a distinct gene expression profile, after stimulation, characterized by dysregulation of immune and signalling pathways. Functionally, these molecular alterations translated into a diminished secretion of key inflammation and infection mediators, such as interleukin-6 (IL-6) and C-C Motif chemokine ligand 5 (CCL5) upon TNF-a stimulation. Similarly, essential signalling kinases including extracellular-signal-regulated kinase (ERK) 1/2, p38 and c-Jun N- terminal kinase (JNK) 2 showed reduced expression in PMM2-CDG cells, and their expression did not alter following TNF-a stimulation, unlike control cells.
Conslusion: Our findings point to TNFR1 signalling dysregulation as a key contributor to immune dysfunction in PMM2-CDG. Importantly, our study identifies TNFR1 as a promising therapeutic target, suggesting that strategies aimed at modulating TNFR1 activity or restoring glycosylation homeostasis could provide new approaches for treatment development. This work advances our understanding of PMM2 -CDG immunopathology and opens opportunities for targeted therapeutics.

Keywords:  PMM2-CDG; TNF-α; fibroblasts; glycomics; inflammation; transcriptomics

DOI:  https://doi.org/10.3389/fimmu.2025.1655354
Mol Syndromol. 2025 Jul 09.

A Treatable Cause of Seizures and Hyperphosphatasia: Patients with PGAP2 and PGAP3 Mutations.

Ezgi Burgac, Merve Yoldas Celik, Burcu Köseci, Habibe Koc Ucar.

   Introduction: Hyperphosphatasia with mental retardation syndrome (HPMRS) is characterized by intellectual impairment, seizures, hypotonia, facial dysmorphism, and elevated serum alkaline phosphatase (ALP) level. HPMRS has been linked to mutations in several genes including PGAP2 and PGAP3. Here, we report 2 patients of HPMRS3 and HPMRS4 and highlight the genetic and phenotypic diversity of this disorder.
Case Reports: Patient 1, a 1-year-old male with developmental delay, generalized tonic-clonic seizures, and dysmorphic facial features, was found to have a pathogenic variant in the PGAP3 gene. Patient 2, a 1-year-old female with seizures, hypotonia, joint hypermobility, and facial dysmorphism, was found to have a pathogenic variant in the PGAP2 gene. Both patients exhibited elevated ALP levels. Brain MRI of patient 1 revealed periventricular hyperintense signal foci, while patient 2 showed cerebral atrophy and basal ganglia diffusion restriction.
Discussion: HPMRS3 and HPMRS4 share clinical features including elevated ALP levels, developmental delay, seizures, and facial dysmorphisms. Although joint hypermobility is not a common feature of HPMRS3, it was observed in our patients. Both patients responded well to high-dose pyridoxine, suggesting a potential therapeutic benefit for seizure management. This report expands the understanding of HPMRS by presenting novel genetic findings and providing insights into the clinical presentation of PGAP2- and PGAP3-related conditions.

Keywords:  Congenital glycosylation defects; Hyperphosphatasia; PGAP2 gene; PGAP3 gene; Seizures

DOI:  https://doi.org/10.1159/000547293
Mol Syndromol. 2025 Oct;16(5): 476-488

Homozygous PGAP2 Mutation Causes Hyperphosphatasia with Mental Retardation Syndrome-3: Genetic and Clinical Evaluation of the Ultra-Rare Inherited Glycosylphosphatidylinositol Biosynthesis Defect.

Aynur Küçükçongar Yavaş, Sümeyra Zeynep Özbey, Bora Ergin, Yasemin Ünal, Berrak Bilginer Gürbüz, Betül Karaatmaca, Hamit Özyürek, Ofcan Oflaz, Hacer Basan, Çiğdem Seher Kasapkara.

   Introduction: Inherited glycosylphosphatidylinositol biosynthesis defect is considered a subset of the congenital glycosylation disorder that results from mutations in the genes encoding proteins participating in glycosylphosphatidylinositol biosynthesis and modification. Glycosylphosphatidylinositol anchor proteins play important roles in numerous cellular processes including neurogenesis, cell adhesion, immune response, and signaling. Hyperphosphatasia with mental retardation syndrome-3 is one of the glycosylphosphatidylinositol anchor defects, characterized by moderate to severe intellectual disability, dysmorphic features, hypotonia, seizures, and persistent hyperphosphatasia. The aims of this study were to investigate the clinical implications of the PGAP2 gene and identify the severe phenotype.
Case Presentation: A male patient with dysmorphic features, neurodevelopmental delay, seizures, hearing loss, Hirschsprung disease, central fever, and elevated alkaline phosphatase was included in the study. The magnetic resonance imaging showed cerebral atrophy and corpus callosum hypoplasia. The whole-exome sequencing analysis of the individual and Sanger sequencing were performed for segregation. Additionally, next-generation sequencing, whole transcriptome sequencing, and homology modeling and analysis were performed. Whole-exome sequencing revealed a homozygous c.651C>G (p.His217Gln) in the PGAP2 gene. The Sanger sequencing confirmed the parents were heterozygous. There is no splicing variant detected by whole transcriptome sequencing. The AlphaFold model was interpreted hypothetically. It observed the substitution of histidine, with glutamine, and may affect the stability of protein.
Discussion: Homozygous PGAP2 mutations in the patient we reported in our study resulted in a severe clinical picture including severe developmental delay and intellectual disability, severe epilepsy, dysmorphic features, central fever, biochemical, hormonal, and immunological abnormalities. This patient would be the youngest case published in the literature. We showed that the instability of mutant PGAP2 protein that causes hyperphosphatasia with mental retardation syndrome-3 leads to more severe phenotypes.

Keywords:  Developmental delay; Glycosylphosphatidylinositol-congenital disorder of glycosylation; Hyperphosphatasia; Hyperphosphatasia mental retardation syndrome-3; PGAP2 mutation

DOI:  https://doi.org/10.1159/000542617
J Cell Biol. 2025 Nov 03. pii: e202509041. [Epub ahead of print]224(11):

A pyrophosphatase that regulates lipid precursors of N-glycosylation.

Anant K Menon.

The oligosaccharide used for protein N-glycosylation in the ER is built as a glycolipid. A recent study by Li, Suzuki, and colleagues (https://doi.org/10.1083/jcb.202501239) identifies a long-sought enzyme that hydrolyzes this lipid as part of a possible homeostatic/quality control mechanism.

DOI: https://doi.org/10.1083/jcb.202509041
Glycoconj J. 2025 Oct 09.

Asparagine-linked glycosylation protein 1 (ALG1) promotes aggressive phenotypes of lung adenocarcinoma cells, A549, via modulating N-linked glycosylation and ER-Stress.

Kanadit Piriyapairoje, Marta Baro, Aanchal Katoch, Bryce De Muth, Ludovica Villanti, Charupong Saengboonmee, Sopit Wongkham, Joseph N Contessa, Chatchai Phoomak.

  Glycosylation plays a critical role in various biological processes and is essential for cell survival. Aberrant glycosylation has been implicated in numerous diseases, including cancer. Lung cancer remains the leading cause of cancer-related mortality worldwide. The correlation between lung cancer progression and abnormal glycosylation has been demonstrated previously. Asparagine-linked glycosylation protein 1 (ALG1) is a key enzyme involved in the N-linked glycosylation process; however, its role in cancer progression remains unclear. In this study, we investigated the function of ALG1 in lung cancer progression. Analysis of the Cancer Genome Atlas (TCGA) dataset revealed that ALG1 expression was significantly upregulated in lung tumor tissues and was associated with poor patient prognosis. To explore its functional relevance, ALG1 expression was depleted in A549 lung adenocarcinoma cells using CRISPR-Cas9-mediated knockout. Loss of ALG1 led to reduced levels of protein N-linked glycosylation and induced an endoplasmic reticulum (ER)-stress response. Functionally, ALG1 knockout significantly impaired A549 cell proliferation, migration, and invasion, as evidenced by phenotypic assays and molecular markers. Moreover, the extent of glycosylation deficiency was positively correlated with ER-stress activation and inversely associated with cancer cell aggressiveness. These findings suggest that ALG1 promotes lung cancer aggressiveness through the regulation of protein glycosylation and modulation of ER-stress pathways. Overall, this study highlights the potential of ALG1 as a therapeutic target and a prognostic biomarker for lung adenocarcinoma patients.

Keywords:  Asparagine-linked glycosylation 1; Cancer progression; Lung adenocarcinoma; N-glycosylation

DOI:  https://doi.org/10.1007/s10719-025-10198-7
Curr Opin Nephrol Hypertens. 2025 Oct 06.

SLC26A1 directs sulfate homeostasis in health and disease.

Felix Pitzken, Anna Köttgen, Peter S Aronson, Felix Knauf.

   PURPOSE OF REVIEW: Sulfate is essential for the sulfation of proteoglycans to maintain cell function. The mechanisms regulating the 'ins and outs' of systemic sulfate balance remain incompletely understood. SLC26A1 is an anion exchanger expressed in the kidney. It has recently been identified as a key regulator of plasma sulfate homeostasis in humans. This review summarizes current insights into SLC26A1 function and its role in human diseases.
RECENT FINDINGS: Slc26a1-knockout mouse models exhibit reduced plasma sulfate and abnormal sulfate and oxalate homeostasis, accompanied by augmented susceptibility to acetaminophen-induced liver injury and kidney stone disease, although findings on oxalate homeostasis are inconsistent. In humans, rare and common SLC26A1 variants are associated with hyposulfatemia, musculoskeletal abnormalities, and, in some cases, nephrolithiasis. Functional assays confirm disrupted sulfate and oxalate transport of damaging variants. However, the knockout mouse models have been incompletely characterized, and few patients with damaging SLC26A1 variants have been characterized regarding sulfate and oxalate homeostasis and associated diseases.
SUMMARY: SLC26A1 emerges as a key regulator of sulfate homeostasis, with potential roles in hepatic detoxification, skeletal integrity, and kidney stone disease. Additional mouse models with tissue-specific gene deletion are needed to delineate the role of SLC26A1 in sulfate and oxalate homeostasis as well as disease pathogenesis. Identification of additional patients with damaging variants in SLC26A1 as well as larger population studies may help to elucidate causal relationships of SLC26A1 activity with clinical outcomes.

Keywords:  SLC26A1; nephrolithiasis; oxalate transport; skeletal disease; sulfate homeostasis

DOI:  https://doi.org/10.1097/MNH.0000000000001123