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.
Introduction
Intellectual disability (ID) is an early-onset neurodevelopmental condition characterised by deficits in intelligence (IQ < 70) and concomitant defects in adaptive behaviour [1, 2]. An estimated 0.5−3% of the population in the developed world is affected by the condition [3,4,5,6]. Although ID can occur in isolation (nonsyndromic ID), it is often accompanied by a broad spectrum of other mental or physical limitations (syndromic ID). Causes underlying ID are heterogeneous [7,8,9]; and the aetiology of ~30% of ID cases is unknown [9]. Monogenic causes account for 40% of all ID with a genetic component, yet, one of over 800 genes can be involved. Since X-linked genes were shown to be expressed more abundantly in the brain than in any other tissue [10], the X chromosome has a disproportionately higher number of genes implicated in mental ability compared with other chromosomes [11, 12]. Indeed, aberrations in at least 140 genes located on the X chromosome were found to cause X-linked intellectual disability (XLID) [13,14,15,16], although several candidate genes remain controversial [13].
Human O-GlcNAc transferase (OGT), located on the X chromosome (Xq13.1), encodes a 110 kDa protein [17, 18] that is highly conserved from Caenorhabditis elegans to Homo sapiens [19]. OGT catalyses O-linked glycosylation of nuclear, cytosolic, and mitochondrial proteins with β-N-acetylglucosamine (O-GlcNAc), which is an essential protein serine/threonine modification in vertebrata [19,20,21]. Attachment and removal of the O-GlcNAc moiety on mammalian nuclear and cytoplasmic proteins is performed by only two enzymes: OGT and O-GlcNAcase (OGA), respectively (Fig. 3). O-GlcNAcylation is thought to be involved in key cellular processes such as gene regulation and expression [22,23,24], metabolic activity [25], and cell-cycle regulation [26]. Changes in O-GlcNAc homoeostasis have been linked to severe developmental problems and neurodegenerative diseases [27,28,29,30,31,32,33].
OGT is a multi-domain protein characterised by a catalytic domain (CD) at the C-terminus and an N-terminal tetratricopeptide repeat domain (TPR) that is involved in substrate recognition and protein–protein interactions (Fig. 1) [34,35,36]. OGT is essential for mouse embryonic stem cell (mESC) and somatic cell survival [19, 37], whereas ablation of OGT is embryonic lethal in mice [19], zebrafish [38], and Drosophila [39]. Sxc, the gene encoding Drosophila OGT (DmOGT) belongs to the family of homeotic genes, the Polycomb group, which regulate segmentation during development [39,40,41]. Sxc loss of function leads to a super sex combs phenotype in Drosophila [39] and death in the adult pharate stage. Interestingly, in addition to its catalytic function, OGT promotes the proteolytic processing and activation of a chromatin-bound transcriptional co-regulator host cell factor 1 (HCF1) [42, 43].