bims-meglyc 2025-12-14 papers

Issue of 2025–12–14
six papers selected by
Silvia Radenkovic, UMC Utrecht

Hum Mutat. 2025 ;2025 7948771

Insights Into the Pathological Glycosylation Associated With COG6-CDG.

Background and Aims: Congenital disorders of glycosylation (CDG) are rare diseases caused by defects in protein glycosylation. We present an infant with multisystemic clinical involvement, diagnosed with COG6-CDG.
Methods: Serum and transferrin-linked N-glycans, as well as serum and apolipoprotein CIII-linked O-glycans, were analyzed by MALDI mass spectrometry. Mutation analysis was performed by next-generation sequencing. Functional studies assessed COG6 subunit expression, cooperating subunits, and retrograde transport. GlycoWorks RapiFluor-MS-based N-glycan labeling with HPLC-FLD and ESI-Orbitrap mass spectrometry enabled further comprehensive glycoprofile analysis.
Results: Aberrant glycosylation typical of combined N- and O-glycosylation defects was detected. Mutation analysis identified a novel homozygous variant in the COG6 gene: c.906_907delinsA, p.(His302GlnfsTer4), introducing a premature stop codon and producing a truncated protein of only 304 amino acids. The diagnosis of COG6-CDG was confirmed by the complete absence of the COG6 subunit, impairment of two other cooperating subunits, and delayed retrograde transport. Independent glycoprofile analyses by HPLC-FLD and ESI-Orbitrap revealed a set of potential glycobiomarkers of COG6-CDG, including underprocessed N-glycans Hex3-5HexNAc2, Hex3-5HexNAc3, Hex3-4HexNAc4, and Hex4HexNAc3-4NeuAc1.
Conclusion: This study describes a novel COG6 variant leading to complete loss of protein function and major glycosylation abnormalities. Multiomics analysis provided deeper insights into the molecular mechanisms of this rare disease and the function of the COG6 gene and demonstrated how the mutation results in significant alterations in the patient's (glyco)phenotype.

Keywords: COG6-CDG; glycomics; glycoprofile; mass spectrometry

DOI: https://doi.org/10.1155/humu/7948771

Int J Mol Sci. 2025 Nov 28. pii: 11560. [Epub ahead of print]26(23):

Beatrice Risso, Antonella Riva, Greta Volpedo, Valerio Conti, Clara Tuccari di San Carlo, Federico Zara, Pasquale Striano, Antonio Falace.

SLC35A2 encodes the Golgi uridine diphosphate galactose transporter, which is essential for glycosylation of glycoproteins and glycolipids. Variants in this gene, either germline or somatic, have emerged as causes of diverse neurological disorders ranging from congenital disorders of glycosylation (SLC35A2-CDG) to focal cortical malformations such as mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy (MOGHE). This review summarizes the molecular function of SLC35A2, clinical phenotypes of congenital and somatic variants, insights from functional assays and animal models, and therapeutic perspectives including galactose supplementation and precision medicine. We aim to provide an integrative synthesis of human genetics, neuropathology, glycomics, and translational approaches.

Keywords: MOGHE; SLC35A2; epilepsy

DOI: https://doi.org/10.3390/ijms262311560

Life Sci. 2025 Dec 04. pii: S0024-3205(25)00777-5. [Epub ahead of print]385 124141

Disorders in sialic acid metabolism and sialylation pathway.

Xue-Long Sun.

Sialic acids (Sias) are acidic 9‑carbon monosaccharides. Both free Sias and conjugated Sias (sialylation) exist in the human body and have decisive impacts on human health and disease. Cellular free Sias are made via de novo biosynthesis, recycled from lysosomal salvage, and even by uptake of extracellular Sias, respectively. Sialylation of glycoproteins and glycolipids are catalyzed by sialyltransferases using CMP-Sia as the donor in the Golgi apparatus. In addition, free Sia can be degraded/catabolized into ManNAc and pyruvate in the cytosol. Overall, cellular free Sia and sialylation are kept at certain levels for normal cell functions. However, Sias deficiency and overproduction (accumulation), hyposialylation (undersialylation) and hypersialylation all cause disorders in the human body through a variety of mechanisms, but most of them are still not fully clarified. This review discusses recent understanding of disorders in Sia biosynthesis, salvage, catabolism, and sialylation pathways and therapeutic explorations for these disorders as well.

Keywords: Metabolism; Myopathy; Sialic acid; Sialidosis; Sialuria; Sialylation

DOI: https://doi.org/10.1016/j.lfs.2025.124141

Glycobiology. 2025 Dec 12. pii: cwaf087. [Epub ahead of print]

Activity of α1,6-fucosyltransferase (FUT8) is reduced by depletion of oligosaccharyltransferase subunits.

Seita Tomida, Takahiro Yamasaki, Daisuke Kohda, Yasuhiko Kizuka.

Alpha-1,6-fucosyltransferase (FUT8) transfers fucose to the innermost GlcNAc residue of N-glycans, forming the core fucose structure. Core fucose critically regulates the functions of various glycoproteins and is associated with several diseases, including chronic obstructive pulmonary disease and cancer. However, the regulatory mechanisms of its enzymatic activity and the intracellular localization of FUT8 remain largely unknown. We previously demonstrated that ribophorin I (RPN1), a subunit of the oligosaccharyltransferase (OST) complex, interacts with FUT8 and positively regulates the enzymatic activity of FUT8; however, it remains unclear whether other OST subunits interact with FUT8 and regulate FUT8 activity. In this study, we assessed the enzymatic activity of FUT8 with knockdown of each OST subunit and showed that silencing ribophorin II (RPN2) as well as RPN1 significantly reduced FUT8 activity. By contrast, no significant effect on FUT8 activity was observed by depleting STT3A and STT3B, which are catalytic subunits of OST, suggesting that the regulation of FUT8 activity by OST is irrelevant to the N-glycosylation activity of OST. Furthermore, various OST subunits were detected in anti-FUT8-immunoprecipitates, and FUT8 was detected in STT3s-dependent high molecular weight complexes in native-PAGE, whereas FUT8 at steady state was mainly localized in the Golgi apparatus, distinct from the endoplasmic reticulum localization of OST. These results suggest that FUT8 transiently interacts with OST complexes during transport in cells. Our findings provide insights into both the intracellular regulatory mechanisms of FUT8 activity and some unexplored functions of OST subunits.

Keywords: FUT8; N-linked glycosylation; glycosyltransferase; oligosaccharyltransferase; core fucose

DOI: https://doi.org/10.1093/glycob/cwaf087

J Pediatr Hematol Oncol. 2025 Nov 20.

Yeter Düzenli Kar, Melike Sezgin Evim, Ugur Cem Mete, Durdugül Ayyildiz Emecan, Tahir Atik, Adalet Meral Güneş.

BACKGROUND: GNE mutations are rare pathologic conditions that can cause severe thrombocytopenia and bleeding tendency from the neonatal period. The clinical presentation of patients with GNE mutations varies from mild skin and mucosal bleeding to life-threatening bleeding.
CASE PRESENTATION: This study reported two siblings with hereditary thrombocytopenia. The 2 patients exhibited severe thrombocytopenia (platelet [PLT] count: <15,000/mm3) since the neonatal period and did not respond to intravenous immunoglobulin (IVIG) and steroids. The patients required PLT transfusions once every 1 to 2 weeks due to frequent bleeding incidence. Whole-exome sequencing was performed based on the preliminary diagnosis of inherited thrombocytopenia. A homozygous missense variant (c.1675G>A [p.Gly559Arg]) was detected in GNE. One sibling was unresponsive to the platelet receptor agonists eltrombopag and romiplostim. Meanwhile, the other sibling was unresponsive to eltrombopag but was responsive to romiplostim.
CONCLUSION: The first-line treatment of patients with GNE mutations is PLT transfusion. However, the management of patients with severe thrombocytopenia and frequent bleeding is challenging. Thrombopoietin receptor agonists are administered to these patients to mitigate the risk of alloimmunization and PLT transfusion refractoriness. However, the observed responses may differ even in siblings carrying the same mutation. This differential response may be related to bone marrow megakaryocyte reserves and hepatocyte Aswell-Morell receptor levels.

Keywords: UDP-N-acetyl-glucosamine 2-epimerase/N-acetylmannosamine kinase (GNE); inheried thrombocytopenia; p.Gly559Arg; sialic acid; siblings

DOI: https://doi.org/10.1097/MPH.0000000000003146

JACC Case Rep. 2025 Dec 12. pii: S2666-0849(25)03079-7. [Epub ahead of print] 106293

Autosomal-Recessive LMNA Dilated Cardiomyopathy.

Rosalie M Sterner, Lea M Coon, John L Black, Ann M Moyer, Joseph J Maleszewski, Linnea M Baudhuin.

BACKGROUND: Variants in the LMNA gene (which encodes intermediate filaments lamin A and lamin C) result in a variety of phenotypes that include overlapping features, such as progeroid syndromes, muscular dystrophies, peripheral neuropathies, lipodystrophies, and cardiac disease (including dilated cardiomyopathy and conduction disorders).
CASE SUMMARY: We describe a case of primary biventricular, nonischemic dilated cardiomyopathy and no myopathic symptoms with a homozygous LMNA c.991C>T (p.Arg331Trp) likely pathogenic variant. The patient, a 39-year-old woman, presented with symptoms of dilated cardiomyopathy and has had ablation, medical management, and a pacemaker placed because of arrythmias.
DISCUSSION: Most LMNA disorders are inherited in an autosomal-dominant fashion, with rare autosomal-recessive laminopathies mainly involving neuromuscular phenotypes. Laminopathies that have involved cardiomyopathies have all been reported to be autosomal dominant.
TAKE-HOME MESSAGE: To our knowledge, this is the first reported case of an autosomal-recessive laminopathy with primary dilated cardiomyopathy.

Keywords: LMNA; autosomal recessive; dilated cardiomyopathy; lamin A/C; laminopathy

DOI: https://doi.org/10.1016/j.jaccas.2025.106293