bims-meglyc 2023-06-25 papers

Dis Model Mech. 2023 06 01. pii: dmm049132. [Epub ahead of print]16(6):

An O-GlcNAc transferase pathogenic variant linked to intellectual disability affects pluripotent stem cell self-renewal.

Michaela Omelková, Christina Dühring Fenger, Marta Murray, Trine Bjørg Hammer, Veronica M Pravata, Sergio Galan Bartual, Ignacy Czajewski, Allan Bayat, Andrew T Ferenbach, Marios P Stavridis, Daan M F van Aalten.

O-linked β-N-acetylglucosamine (O-GlcNAc) transferase (OGT) is an essential enzyme that modifies proteins with O-GlcNAc. Inborn OGT genetic variants were recently shown to mediate a novel type of congenital disorder of glycosylation (OGT-CDG), which is characterised by X-linked intellectual disability (XLID) and developmental delay. Here, we report an OGTC921Y variant that co-segregates with XLID and epileptic seizures, and results in loss of catalytic activity. Colonies formed by mouse embryonic stem cells carrying OGTC921Y showed decreased levels of protein O-GlcNAcylation accompanied by decreased levels of Oct4 (encoded by Pou5f1), Sox2 and extracellular alkaline phosphatase (ALP), implying reduced self-renewal capacity. These data establish a link between OGT-CDG and embryonic stem cell self-renewal, providing a foundation for examining the developmental aetiology of this syndrome.

Keywords: O-GlcNAc; Congenital disorders of glycosylation; Intellectual disability; OGT; Self-renewal; Stem cells

DOI: https://doi.org/10.1242/dmm.049132

J Inherit Metab Dis. 2023 Jun 21.

Oral sialic acid supplementation in NANS-CDG: Results of a single center, open label, observational pilot study.

Bibiche den Hollander, Marion M Brands, Lonneke de Boer, Charlotte Haaxma, Anna Lengyel, Peter van Essen, Gera Peters, Hanneke J T Kwast, Willemijn M Klein, Karlien L M Coene, Dirk J Lefeber, Clara D M van Karnebeek.

BACKGROUND: NANS-CDG is a congenital disorder of glycosylation (CDG) caused by biallelic variants in NANS, encoding an essential enzyme in de novo sialic acid synthesis. It presents with intellectual developmental disorder (IDD), skeletal dysplasia, neurologic impairment, and gastrointestinal dysfunction. Some patients suffer progressive intellectual neurologic deterioration (PIND), emphasizing the need for a therapy. In a previous study, sialic acid supplementation in knockout nansa zebrafish partially rescued skeletal abnormalities. Here, we performed the first in-human pre- and postnatal sialic-acid study in NANS-CDG.METHODS: In this open-label observational study, 5 patients with NANS-CDG (range 0 - 28 years) were treated with oral sialic acid for 15 months. Primary outcome was safety. Secondary outcomes were psychomotor / cognitive testing, height and weight, seizure control, bone health, gastrointestinal symptoms and biochemical and hematological parameters.
RESULTS: Sialic acid was well tolerated. In postnatally treated patients, there was no significant improvement. For the prenatally treated patient, psychomotor and neurologic development was better than two other genotypically identical patients (one treated postnatally, one untreated).
CONCLUSIONS: The effect of sialic acid treatment may depend on the timing, with prenatal treatment potentially benefiting neurodevelopmental outcomes. Evidence is limited however, and longer-term follow-up in a larger number of prenatally treated patients is required. This article is protected by copyright. All rights reserved.

Keywords: Congenital Disorder of Glycosylation; N-acetyl-D-neuraminic acid; glycosylation; inherited metabolic disorder; intellectual developmental disorder; personalized medicine; sialic acid biosynthesis

DOI: https://doi.org/10.1002/jimd.12643

Biochim Biophys Acta Gen Subj. 2023 Jun 20. pii: S0304-4165(23)00110-1. [Epub ahead of print] 130412

Metalloglycobiology: The power of metals in regulating glycosylation.

Zoé Durin, Marine Houdou, Dominique Legrand, François Foulquier.

The remarkable structural diversity of glycans that is exposed at the cell surface and generated along the secretory pathway is tightly regulated by several factors. The recent identification of human glycosylation diseases related to metal transporter defects opened a completely new field of investigation, referred to herein as "metalloglycobiology", on how metal changes can affect the glycosylation and hence the glycan structures that are produced. Although this field is in its infancy, this review aims to go through the different glycosylation steps/pathways that are metal dependent and that could be impacted by metal homeostasis dysregulations.

Keywords: CDG; Glycosylation; Metals; Regulation

DOI: https://doi.org/10.1016/j.bbagen.2023.130412

Ageing Res Rev. 2023 Jun 20. pii: S1568-1637(23)00150-2. [Epub ahead of print] 101991

Protein glycosylation and glycoinformatics for novel biomarker discovery in neurodegenerative diseases.

Júlia Costa, Catherine Hayes, Frédérique Lisacek.

Glycosylation is a common post-translational modification of brain proteins including cell surface adhesion molecules, synaptic proteins, receptors and channels, as well as intracellular proteins, with implications in brain development and functions. Using advanced state-of-the-art glycomics and glycoproteomics technologies in conjunction with glycoinformatics resources, characteristic glycosylation profiles in brain tissues are increasingly reported in the literature and growing evidence shows deregulation of glycosylation in central nervous system disorders, including aging associated neurodegenerative diseases. Glycan signatures characteristic of brain tissue are also frequently described in cerebrospinal fluid due to its enrichment in brain-derived molecules. A detailed structural analysis of brain and cerebrospinal fluid glycans collected in publications in healthy and neurodegenerative conditions was undertaken and data was compiled to create a browsable dedicated set in the GlyConnect database of glycoproteins (https://glyconnect.expasy.org/brain). The shared molecular composition of cerebrospinal fluid with brain enhances the likelihood of novel glycobiomarker discovery for neurodegeneration, which may aid in unveiling disease mechanisms, therefore, providing with novel therapeutic targets as well as diagnostic and progression monitoring tools.

Keywords: Biomarker; brain; cerebrospinal fluid; glycoinformatics; neurodegeneration; protein glycosylation

DOI: https://doi.org/10.1016/j.arr.2023.101991