Biochemical Characterization of Missense Mutations in O‐GlcNAc Transferase Found in Patients With X‐Linked Intellectual Disability

Abstract

O‐GlcNAc is an abundant post‐translational modification of nucleocytoplasmic proteins that has been implicated in biological processes such as transcription, cell‐cycle regulation, and nutrient‐sensing. O‐GlcNAc transferase (OGT) catalyzes the reversible transfer of the monosaccharide N‐acetylglucosamine (GlcNAc) from the donor substrate UDP‐GlcNAc to serine and threonine residues on nuclear, cytosolic, and mitochondrial substrates, while the enzyme O‐GlcNAcase (OGA) reverses this process. OGT consists of a tetratricopeptide repeat (TPR) region and catalytic domains, both of which are required for substrate glycosylation. Through exome sequencing of multiple patient samples, 5 individual missense mutations in the TPR region of OGT appear causal for X‐linked intellectual disability (XLID). However, the effect of each of these mutations on enzyme characteristics is poorly understood. To elucidate the mechanism through which each mutation causes development of XLID, the recombinant, purified OGT variants are being biochemically characterized. We are currently in the process of defining the differential interactome/O‐GlcNAc proteome of OGT variants using quantitative glycoproteomic approaches and performing functional assays to identify processes linking OGT to XLID.Support or Funding InformationThis work is funded by grants from the Keck Foundation and the NIH (P41GM103490) to Dr. Lance Wells.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.