Intellectual disability (ID) is a neurodevelopmental condition that affects~1% of the world population. In total 5−10% of ID cases are due to variants in genes located on the X chromosome. Recently, variants in OGT have been shown to co-segregate with X-linked intellectual disability (XLID) in multiple families. OGT encodes O-GlcNAc transferase (OGT), an essential enzyme that catalyses O-linked glycosylation with β-N-acetylglucosamine (O-GlcNAc) on serine/threonine residues of thousands of nuclear and cytosolic proteins. In this review, we compile the work from the last few years that clearly delineates a new syndromic form of ID, which we propose to classify as a novel Congenital Disorder of Glycosylation (OGT-CDG). We discuss potential hypotheses for the underpinning molecular mechanism(s) that provide impetus for future research studies geared towards informed interventions.

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Glycan biosynthesis relies on nucleotidesugars (NS), abundant metabolites that serve as monosaccharide donors for glycosyltransferases. In vivo, signal-dependent fluctuations in NS levels are required to maintain normal cell physiology and are dysregulated in disease, but how mammalian cells regulate NS levels and pathway flux remains largely uncharacterized. To address this knowledge gap, we examined uridine diphosphate (UDP)galactose 4'-epimerase (GALE), which interconverts two pairs of essential NSs. GALE deletion in human cells triggered major imbalances in its substrate NSs and consequent dramatic changes in glycolipids and glycoproteins, including a subset of integrins and the Fas death receptor. NS dysregulation also directly impacted cell signaling, as GALE -/cells exhibit Fas hypoglycosylation and hypersensitivity to Fas ligand-induced apoptosis. Our results reveal a new role for GALE-mediated NS regulation in supporting death receptor signaling and may have implications for the molecular etiology of illnesses characterized by NS imbalances, including galactosemia and metabolic syndrome. Control (HeLa)GALE -/-(HeLa)

Glycan biosynthesis relies on nucleotide sugars (NSs), abundant metabolites that serve as monosaccharide donors for glycosyltransferases. In vivo, signal-dependent fluctuations in NS levels are required to maintain normal cell physiology and are dysregulated in disease. However, how mammalian cells regulate NS levels and pathway flux remains largely uncharacterized. To address this knowledge gap, here we examined UDP-galactose 4′-epimerase (GALE), which interconverts two pairs of essential NSs. Using immunoblotting, flow cytometry, and LC-MS–based glycolipid and glycan profiling, we found that CRISPR/Cas9-mediated GALE deletion in human cells triggers major imbalances in NSs and dramatic changes in glycolipids and glycoproteins, including a subset of integrins and the cell-surface death receptor FS-7-associated surface antigen. In particular, we observed substantial decreases in total sialic acid, galactose, and GalNAc levels in glycans. These changes also directly impacted cell signaling, as GALE−/− cells exhibited FS-7-associated surface antigen ligand-induced apoptosis. Our results reveal a role of GALE-mediated NS regulation in death receptor signaling and may have implications for the molecular etiology of illnesses characterized by NS imbalances, including galactosemia and metabolic syndrome.

Nucleotide‐sugars are required for glycosylation reactions in mammals, but it is largely unknown how their levels are dynamically regulated in response to cellular signals. The UDP‐galactose 4’‐epimerase (GalE) has recently emerged as a potential regulator of nucleotide‐sugar flux in response to stimuli such as feeding, ischemia and endoplasmic reticulum (ER) stress. The importance of this enzyme is underscored by human patients with hypomorphic GalE alleles, constituting a disease termed type III galactosemia. Critically, the molecular underpinnings of galactosemic pathophysiology are unclear.Because it controls the levels of multiple substrates in several signaling contexts, GalE is an ideal candidate for studying the importance of nucleotide‐sugar regulation in both normal and disease physiology. In this work, we generated GalE−/− human cell lines using CRISPR‐Cas9 mutagenesis. We characterized the effects of GalE loss on nucleotide‐sugar metabolism, protein glycosylation, and death receptor function. Our results demonstrate that loss of the GalE enzyme effects dramatic dysfunction in nucleotide‐sugar metabolism along with protein and lipid glycosylation. We have observed mis‐glycosylation of various cell‐surface proteins. GalE−/− human cells exhibit dysregulated cellular signaling, which we hypothesize is due to mis‐glycosylation of cell‐surface receptors.Support or Funding InformationResearch in the Boyce Lab has been supported by NIH grants R01GM118847 and R01GM117473 and the Rita Allen Foundation Scholars programThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.