Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/113756
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Type: Journal article
Title: O-GlcNAc transferase missense mutations linked to X-linked intellectual disability deregulate genes involved in cell fate determination and signaling
Author: Selvan, N.
George, S.
Serajee, F.
Shaw, M.
Hobson, L.
Kalscheuer, V.
Prasad, N.
Levy, S.
Taylor, J.
Aftimos, S.
Schwartz, C.
Huq, A.
Gecz, J.
Wells, L.
Citation: Journal of Biological Chemistry, 2018; 293(27):10810-10824
Publisher: American Society for Biochemistry and Molecular Biology
Issue Date: 2018
ISSN: 0021-9258
1083-351X
Statement of
Responsibility: 
Nithya Selvan, Stephan George, Fatema J. Serajee, Marie Shaw, Lynne Hobson, Vera Kalscheuer, Nripesh Prasad, Shawn E. Levy, Juliet Taylor, Salim Aftimos, Charles E. Schwartz, Ahm M. Huq, Jozef Gecz, and Lance Wells
Abstract: It is estimated that ~1% of the world's population has intellectual disability, with males affected more often than females. OGT is an X-linked gene encoding for the enzyme O-GlcNAc transferase (OGT), which carries out the reversible addition of N-Acetylglucosamine (GlcNAc) to Ser/Thr residues of its intracellular substrates. Three missense mutations in the tetratricopeptide (TPR) repeats of OGT have recently been reported to cause X-linked Intellectual Disability (XLID). Here we report the discovery of two additional novel missense mutations (c. 775 G>A, p. A259T and c. 1016 A>G, p. E339G) in the TPR domain of OGT that segregate with XLID in affected families. Characterization of all five of these XLID missense variants of OGT demonstrates modest declines in thermodynamic stability and/or activities of the variants. We engineered each of the mutations into a male human embryonic stem cell line using CRISPR/Cas9. Investigation of the global O-GlcNAc profile as well as OGT and OGA levels by Western blotting showed no gross changes in steady-state levels in the engineered lines.  However, analyses of the differential transcriptomes of the OGT variant expressing stem cells revealed shared deregulation of genes involved in cell fate determination and LXR/RXR signaling, which has been implicated in neuronal development. Thus, here we reveal 2 additional mutations encoding residues in the TPR regions of OGT that appear causal for XLID and provide evidence that the relatively stable and active TPR variants may share a common, unelucidated, mechanism of altering gene expression profiles in human embryonic stem cells.
Keywords: O-linked N-acetylglucosamine (O-GlcNAc)
Description: Published, Papers in Press, May 16, 2018.
Rights: © 2018 Selvan et al. Published under exclusive license by The American Society for Biochemistry and Molecular Biology, Inc.
RMID: 0030088804
DOI: 10.1074/jbc.RA118.002583
Grant ID: http://purl.org/au-research/grants/nhmrc/1091593
http://purl.org/au-research/grants/nhmrc/1041920
Appears in Collections:Medicine publications

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