An intellectual disability syndrome with single-nucleotide variants in O-GlcNAc transferase

Veronica M Pravata,Michaela Omelková,Katrin Õunap,Jozef Gecz,Charles E Schwartz,Lance Wells,Mehmet Gundogdu,Marios P Stavridis,Dirk J Lefeber,Shelagh Joss,Chelsea M Desbiens,Hannah M Stephen,Daan M F Van Aalten

doi:10.1038/s41431-020-0589-9

Abstract

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.

Highlights

Intellectual disability (ID) is an early-onset neurodevelopmental condition characterised by deficits in intelligence (IQ < 70) and concomitant defects in adaptive behaviour [1, 2]
O-GlcNAc transferase (OGT) and O-GlcNAcylated proteins are present in both postand presynaptic terminals, and O-GlcNAc modified proteins account for 40% of all neuronal proteins and 19% of synaptosome proteins [48]
RT-qPCR analysis of GABPA, a known target of host cell factor 1 (HCF1) and known to mediate synapse-specific gene expression [58], showed increased levels of the gene [32]. These results suggest that there may be an association between OGT-X-linked intellectual disability (XLID) variants and HCF1 processing

Summary

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Intellectual disability (ID) is an early-onset neurodevelopmental condition characterised by deficits in intelligence (IQ < 70) and concomitant defects in adaptive behaviour [1, 2]. Variants in OGT may lead to reduction of OGA protein/transcript to maintain O-GlcNAc homoeostasis This opens the possibility that the OGT-XLID phenotypes are caused by reduced expression of a functional OGA. A possible hypothesis behind the OGT-related XLID phenotypes is that HCF1 is misprocessed To explore this link, HCF1 processing activity of OGT and the XLID variants has been explored in vitro using recombinant mutant enzymes (Table 2). Missense variants in many genes lead to protein misfolding and aggregation, which is toxic to terminally differentiated neurons that entirely rely on proteolytic processing to resolve such aggregates Another potential mechanism underlying the OGT-related XLID phenotype is that the OGT-XLID variants are unstable and/or aggregate. Defining the O-GlcNAcome and OGlcNAc cycling rates, will be essential to evaluate the role of catalytic OGT variants in this hypothesis

Discussion

Findings

Compliance with ethical standards