bims-meglyc 2025-09-28 papers

Issue of 2025–09–28
four papers selected by
Silvia Radenkovic, UMC Utrecht

Orphanet J Rare Dis. 2025 Sep 24. 20(1): 484

Zebrafish models for congenital disorders of glycosylation (CDG): a systematic review.

N Gandoy-Fieiras, M I Quiroga, L Sánchez.

Glycosylation is a post-translational modification of proteins that involves the addition of glycan groups and is essential for their proper functionality. This highly complex process affects 70% of all human proteins. Mutations in genes involved in glycosylation pathways can lead to a group of rare genetic syndromes known as Congenital Disorders of Glycosylation (CDG). One of the workflows applied to study human diseases includes animal models, such as the zebrafish. This systematic review aims to explore the utility of the zebrafish model in studying congenital disorders of glycosylation. For this purpose, searches were conducted in PubMed, Web of Science, and Scopus using terms related to congenital disorders of glycosylation and zebrafish, covering studies published up to November 2024. A total of 36 articles were identified based on the inclusion criteria. The results provide a comprehensive overview of these studies. The analysis reveals that CDGs related to N-glycosylation are the most frequently studied, morpholinos are the predominant technique used, zebrafish glycosylation genes exhibit a high degree of homology with human genes, and zebrafish models successfully replicate many of the clinical features observed in human CDG patients. This review highlights that zebrafish is a valuable strategy for studying CDG, offering important insights into the pathophysiology of these disorders and contributing to the development of potential therapeutic approaches.

Keywords: Animal model; CDG; Congenital disorder of glycosylation; Disease model; Glycosylation; Zebrafish

DOI: https://doi.org/10.1186/s13023-025-04016-4

Biomolecules. 2025 Aug 29. pii: 1256. [Epub ahead of print]15(9):

Neuromuscular Defects in a Drosophila Model of the Congenital Disorder of Glycosylation SLC35A2-CDG.

Kazuyoshi Itoh, Masaki Kurogochi, Tadashi Kaname, Jun-Ichi Furukawa, Shoko Nishihara.

SLC35A2-CDG is a congenital disorder of glycosylation caused by mutations in the SLC35A2 gene encoding a Golgi-localized UDP-galactose transporter. This transporter plays an essential role in glycan synthesis by transporting UDP-galactose from the cytoplasm into the Golgi lumen. Its dysfunction leads to impaired galactose-containing glycans and various neurological symptoms, although the underlying mechanisms remain largely unknown. We identified a novel SLC35A2-CDG patient carrying a pathogenic variant (c.617_620del, p.(Gln206ArgfsTer45)) who exhibited neurological abnormalities including bilateral ventriculomegaly. To investigate the disease mechanism, we established the first Drosophila model of SLC35A2-CDG. Knockout of Ugalt, the fly ortholog of SLC35A2, resulted in embryonic lethality, indicating its essential role. Knockdown of Ugalt reduced mucin-type O-glycans on muscles and neuromuscular junctions (NMJs), without affecting N-glycans. Ugalt knockdown larvae exhibited mislocalized NMJ boutons accompanied by a deficiency in basement membrane components on muscles. This phenotype resembles that of mutants of dC1GalT1 and dGlcAT-P, both involved in mucin-type O-glycosylation. Genetic interaction between Ugalt and dC1GalT1 was confirmed through double knockdown and double heterozygous analyses. Given that Drosophila NMJs are widely used as a model for mammalian central synapses, our findings suggest that Ugalt regulates NMJ architecture via mucin-type O-glycosylation and provide insights into the molecular basis of neurological abnormalities in SLC35A2-CDG.

Keywords: Drosophila; SLC35A2-CDG; T antigen; Ugalt; basement membrane; mucin-type O-glycan; muscle; neuromuscular junction

DOI: https://doi.org/10.3390/biom15091256

J Hum Genet. 2025 Sep 26.

Biosynthesis of GPI anchored proteins, its deficiencies and treatment.

Yoshiko Murakami.

Glycosylphosphatidylinositol (GPI) anchoring is a widely conserved post-translational modification in eukaryotes, in which various proteins-such as receptors, cell adhesion molecules, and complement regulatory proteins-are modified with a GPI moiety and tethered to the cell membrane. GPI anchors are synthesized in the endoplasmic reticulum (ER), where they are attached to newly translated proteins. These GPI-anchored proteins (GPI-APs) then undergo structural remodeling and are transported to the cell surface. To date, approximately 30 gene products have been identified as essential for the GPI biosynthetic and remodeling pathways. In addition to paroxysmal nocturnal hemoglobinuria (PNH), a well-characterized acquired hematologic disorder caused by somatic mutations in GPI biosynthesis genes, an increasing number of inherited GPI deficiencies (IGDs) have recently been reported. These congenital disorders are typically caused by hypomorphic mutations in GPI biosynthetic genes and present with neurological abnormalities. In this review, we provide an overview of the biosynthetic pathway of GPI anchors in mammalian cells and the genetic disorders resulting from its dysfunction. We also discuss emerging therapeutic approaches currently under investigation, including gene therapy, which hold promise for improving clinical outcomes in patients with IGD.

DOI: https://doi.org/10.1038/s10038-025-01379-1

Sci Adv. 2025 Sep 26. 11(39): eadx2407

A sensory and motor neuropathy caused by a genetic variant of NAMPT.

Zhe Zhang, Jacek Pilch, Samuel Lundt, Nannan Zhang, Yongchang Chang, Tracey Singer, Dariusz Śladowski, Xiao-Ling Hu, Lijun Zheng, Woo-Ping Ge, Hua Zhang, De-Pei Li, Xianlin Han, Rafal Ploski, Shinghua Ding.

Nicotinamide phosphoribosyl transferase (NAMPT) is the rate-limiting enzyme in the salvage pathway for nicotinamide adenine dinucleotide (NAD+) biosynthesis in mammalian cells and is essential for survival. Here, we report on a previously unidentified axonal sensory and motor neuropathy likely caused by a homozygous genetic variant of missense mutation (c.472G>C, p.P158A) in the NAMPT gene. Two affected siblings presented with a range of clinical features including impaired motor coordination, muscle atrophy, foot deformities, and positive Babinski sign. Using different preparations including recombinant human and mouse NAMPT proteins, patient fibroblasts, and mouse model, we showed that the p.P158A mutation decreased NAMPT enzyme activity, leading to disrupted cellular bioenergetics, metabolic derangements, and increased oxidative stress. Moreover, the p.P158A mutation could cause synaptic dysfunction and motor neuron degeneration in the mouse model. This Mutation in NAMPT Axonopathy (MINA) syndrome is the first human hereditary neurological disease linking to an NAMPT variant. Our study has substantial clinical implications.

DOI: https://doi.org/10.1126/sciadv.adx2407