bims-meglyc 2025-10-05 papers

Issue of 2025–10–05
five papers selected by
Silvia Radenkovic, UMC Utrecht

Am J Med Genet A. 2025 Oct 01. e64275

An OGT Missense Variant With Impaired Enzyme Activity in a Child With Severe Developmental Delay and Hepatoblastoma.

Alfonso Manuel D'Alessio, Huijie Yuan, Leandro Raul Soria, Sara Basse Hansen, Iolanda Boffa, Paola Arena, Benedetta Attianese, Maureen O'Sullivan, Noelle Cullinan, Lewis Pang, Daan Marinus Ferdinand van Aalten, Nicola Brunetti-Pierri, Sally Ann Lynch.

O-GlcNAc transferase (OGT) and its antagonist O-GlcNAcase (OGA) regulate protein O-GlcNAcylation, a highly conserved post-translational modification involved in metabolic sensing. Pathogenic variants in the OGT gene cause an X-linked congenital disorder of glycosylation (OGT-CDG) presenting developmental delay, hypotonia, intellectual disability, and dysmorphic features. Here, we report on a child with developmental delay, hypotonia, and dysmorphic features who was found to carry a hemizygous novel OGT variant. This child also developed hepatoblastoma by the age of 17 months. OGT-CDG was diagnosed by exome sequencing that identified a de novo missense variant in the OGT gene. Functional validation by Western blot on patient-derived fibroblasts showed reduced O-GlcNAcylation and OGA expression, while significantly reduced enzyme activity in vitro confirmed the pathogenicity of the variant. To date, no patients with OGT-CDGs have been reported with hepatoblastoma or other malignancies. Although the occurrence of hepatoblastoma in the proband might be coincidental, the role of O-GlcNAcylation in cancer suggests that the deficiency of OGT activity might be associated with increased cancer risk.

Keywords: OGT variant; OGT‐CDG; O‐GlcNAc transferase; congenital disorder of glycosylation; hepatoblastoma; intellectual disability; rare disease

DOI: https://doi.org/10.1002/ajmg.a.64275

Mol Genet Metab. 2025 Sep 18. pii: S1096-7192(25)00225-2. [Epub ahead of print]146(3): 109234

Defining the clinical spectrum and genotype-phenotype correlations for CCDC115-CDG: A patient report and review of the literature.

Chloé J Geerts, Fernando Alvarez, Brian M Gilfix, Matthew J Schultz, Philippe M Campeau.

CCDC115-CDG is a recently described combined N- and O-linked congenital disorder of glycosylation affecting Golgi apparatus homeostasis. To date, only thirteen patients have been reported with this condition. The clinical presentation is characterized by hepatosplenomegaly, elevated serum aminotransferases and alkaline phosphatase, often accompanied by psychomotor delay and hypotonia, hypercholesterolemia and copper metabolism anomalies, features that can mimic Wilson disease. Serum transferrin capillary electrophoresis shows a pattern compatible with abnormal Golgi N-glycosylation. We gathered phenotype descriptions and molecular data from all reported patients to better characterize this condition and explore potential genotype-phenotype correlation. Notably, we observed that homozygosity for the p.Leu31Ser variant is associated with higher serum transaminase levels. We also report the natural history of a patient, as clinical narratives are lacking in the literature for this condition. In summary, our report provides new insights into the natural history and genotype-phenotype correlation of CCDC115-CDG, key elements to focus on in ultra-rare conditions.

Keywords: CCDC115-CDG; CDG syndrome; Copper; Liver disease; Transferrin isoelectric focusing; Wilson-like

DOI: https://doi.org/10.1016/j.ymgme.2025.109234

ACS Omega. 2025 Sep 23. 10(37): 43243-43251

Resolving Hexose-Phosphates by LC-MS Leads to New Insights in PGM1-CDG Pathophysiology.

Karen Driesen, Sam De Craemer, Eva Morava, David Cassiman, Peter Witters, Bart Ghesquière.

Hexose-phosphates play a role in many metabolic pathways, such as glycolysis and glycosylation. To understand the molecular basis of diseases such as congenital disorders of glycosylation (CDG), information about the source and abundance of hexose-phosphates is imperative. Mass spectrometry (MS)-based tracer metabolomics can provide this information, but hexose-phosphates are structural isomers with similar physicochemical properties, which makes them difficult to differentiate using MS. Here, we present and compare two optimized liquid-chromatography-based MS methods for the identification of relevant hexose-phosphates, compatible with tracer metabolomics. A combination of these two methods led to the analysis of eight hexose-monophosphates and two hexose-bisphosphates that can occur in humans. Both methods displayed linearity in 3 to 4 orders of magnitude, with limits of quantification between 0.5 and 50 nM, which is well within the cellular concentration range. The applicability of these methods to biological models was then proven in a study of the effect of galactose treatment in phosphoglucomutase 1 (PGM1)-CDG fibroblasts. Here, we show, for the first time, the hexose-phosphate profiles in CDG and how these change upon treatment.

DOI: https://doi.org/10.1021/acsomega.5c07074

Mol Cell Proteomics. 2025 Sep 29. pii: S1535-9476(25)00176-8. [Epub ahead of print] 101077

Zscan4 as a candidate conveyor of early developmental defects in O-GlcNAc transferase intellectual disability.

Veronica M Pravata, Hao Jiang, Andrew T Ferenbach, Angus Lamond, Daan M F van Aalten.

Variants in the human β-N-acetylglucosamine (O-GlcNAc) transferase (OGT) gene give rise to an intellectual disability (ID) syndrome termed OGT congenital disorder of glycosylation (OGT-CDG). The mechanisms by which loss of OGT and/or protein O-GlcNAcylation lead to this syndrome are not understood, but symptoms associated with the syndrome suggest a developmental origin. Here, we establish and characterise two lines of mouse embryonic stem cells carrying different patient mutations and show that these mutations lead to disrupted O-GlcNAc homeostasis. Using quantitative proteomics on these cells in the pluripotent state, we identify candidate proteins/pathways that could underpin this syndrome. In addition to the increased levels of OGT and decreased levels of OGA reflecting disrupted O-GlcNAc homeostasis, we find that expression of the ID gene Zscan4 is upregulated. This is associated with increased levels of the OGT:Ten Eleven (Tet) - protein complex that regulates DNA methylation and Zscan4 expression. These data uncover a potential mechanism contributing to the developmental aspects of OGT-CDG.

DOI: https://doi.org/10.1016/j.mcpro.2025.101077

J Cell Biol. 2025 Nov 03. pii: e202501239. [Epub ahead of print]224(11):

LLP1 is a pyrophosphatase involved in homeostasis/quality control of dolichol-linked oligosaccharide.

Sheng-Tao Li, Katsuhiko Kamada, Akinobu Honda, Junichi Seino, Tsugiyo Matsuda, Takehiro Suzuki, Naoshi Dohmae, Yuichi Shichino, Shintaro Iwasaki, Yoichi Noda, Michael Costanzo, Charles Boone, Tadashi Suzuki.

Dolichol-linked oligosaccharide (DLO) is the precursor for asparagine (N)-linked protein glycosylation. DLO synthesis can be impaired by genetic and environmental factors, leading to the accumulation of various immature DLO intermediates that are subsequently cleaved into phosphorylated oligosaccharides (POSs). Despite the fact that its activity has been known since the 1970s, the identity of the enzyme has not been clarified. Here, we identified a Saccharomyces cerevisiae gene encoding a DLO-pyrophosphatase (Llp1), which converts DLO to POSs. Intriguingly, LLP1 mRNA was translated through a programmed +1 translational frameshifting. LLP1 orthologs encode members of VanZ family proteins, which are found in various bacteria and fungi. Llp1 and its substrate DLO are likely to be localized in the Golgi, and when LLP1 was knocked out, abnormal DLO modified by Golgi mannosyltransferases accumulated, which is consistent with a role in DLO homeostasis/quality control. This study provides insights into how the cellular levels and quality of DLOs are maintained in eukaryotes.

DOI: https://doi.org/10.1083/jcb.202501239