# O-GlcNAc dynamics and the OGT interactome in variants causal for X-linked intellectual disability

> **NIH NIH R21** · UNIVERSITY OF GEORGIA · 2020 · $226,500

## Abstract

PROJECT SUMMARY
X-linked intellectual disability (XLID) affects approximately 1 in 1,000 males. Recently, we have discovered
mutations in the gene encoding O-GlcNAc transferase (OGT) that are causal for XLID. These mutations
generate variants with amino acid substitutions in the TPR domains of OGT that are thought to be involved in
protein-protein interactions. The modification of Ser/Thr residues of nuclear and cytosolic proteins by the
addition of a single glycan (O-linked N-acetylglucosamine, O-GlcNAc) by OGT impacts the stability,
localization, activity, and protein-protein interactions of many nuclear and cytosolic proteins. Similar to
phosphorylation, thousands of nuclear and cytosolic proteins in mammals are modified by O-GlcNAc. Unlike
phosphorylation, which is mediated by a plethora of kinases and a smaller set of phosphatases, O-
GlcNAcylation results from the activity of a single transferase (OGT) and can be removed by a single hydrolase
(O-GlcNAc hydrolase, OGA). It has been suggested that the O-GlcNAc modification is a regulatory
modification in that it has been demonstrated to be globally inducible and dynamic on a small subset of
proteins examined. We hypothesize that the TPR variants observed in XLID are altering O-GlcNAc dynamics
and/or the OGT interactome. The specific aims leverage our expertise in O-GlcNAc biology and the
enzymology of OGT along with our innovative labeling, enrichment, and mass spectrometry-based approaches
for site-mapping and interactome identification applied to neural lineages derived from normal or Cas9-
engineered human embryonic stem cells. In Aim 1, we develop a novel method for examining the dynamics of
both site-specific O-GlcNAc modification and the modified protein and couple this with enrichment strategies
and tandem mass spectrometry approaches to define O-GlcNAc cycling rates in a cell type and XLID genotype
dependent manner. In Aim 2, we define the OGT interactome using classical co-immunoprecipitation as well
as proximity labeling approaches in a cell type and XLID genotype dependent manner. The successful
completion of these aims will not only benefit the O-GlcNAc biology community but more importantly will
identify specific OGT targets and binding partners impacted by XLID for future detailed hypothesis-driven
studies.

## Key facts

- **NIH application ID:** 10011894
- **Project number:** 5R21HD097652-02
- **Recipient organization:** UNIVERSITY OF GEORGIA
- **Principal Investigator:** Lance Wells
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $226,500
- **Award type:** 5
- **Project period:** 2019-09-10 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10011894

## Citation

> US National Institutes of Health, RePORTER application 10011894, O-GlcNAc dynamics and the OGT interactome in variants causal for X-linked intellectual disability (5R21HD097652-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10011894. Licensed CC0.

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