An intellectual disability syndrome with single-nucleotide variants in O-GlcNAc transferase
Veronica M. Pravatà, Michaela Omelková, Marios P. Stavridis, Chelsea Desbiens, Hannah Stephen, Dirk J. Lefeber, Jozef Gécz, Mehmet Gundogdu, Katrin Õunap, Shelagh Joss, Charles E. Schwartz, Lance Wells, Daan M. F. van Aalten
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.