Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/113756
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dc.contributor.authorSelvan, N.en
dc.contributor.authorGeorge, S.en
dc.contributor.authorSerajee, F.en
dc.contributor.authorShaw, M.en
dc.contributor.authorHobson, L.en
dc.contributor.authorKalscheuer, V.en
dc.contributor.authorPrasad, N.en
dc.contributor.authorLevy, S.en
dc.contributor.authorTaylor, J.en
dc.contributor.authorAftimos, S.en
dc.contributor.authorSchwartz, C.en
dc.contributor.authorHuq, A.en
dc.contributor.authorGecz, J.en
dc.contributor.authorWells, L.en
dc.date.issued2018en
dc.identifier.citationJournal of Biological Chemistry, 2018; 293(27):10810-10824en
dc.identifier.issn0021-9258en
dc.identifier.issn1083-351Xen
dc.identifier.urihttp://hdl.handle.net/2440/113756-
dc.descriptionPublished, Papers in Press, May 16, 2018.en
dc.description.abstractIt 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.en
dc.description.statementofresponsibilityNithya 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 Wellsen
dc.language.isoenen
dc.publisherAmerican Society for Biochemistry and Molecular Biologyen
dc.rights© 2018 Selvan et al. Published under exclusive license by The American Society for Biochemistry and Molecular Biology, Inc.en
dc.subjectO-linked N-acetylglucosamine (O-GlcNAc)en
dc.titleO-GlcNAc transferase missense mutations linked to X-linked intellectual disability deregulate genes involved in cell fate determination and signalingen
dc.typeJournal articleen
dc.identifier.rmid0030088804en
dc.identifier.doi10.1074/jbc.RA118.002583en
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1091593en
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1041920en
dc.identifier.pubid421712-
pubs.library.collectionMedicine publicationsen
pubs.library.teamDS03en
pubs.verification-statusVerifieden
pubs.publication-statusPublisheden
dc.identifier.orcidShaw, M. [0000-0002-5060-190X]en
dc.identifier.orcidGecz, J. [0000-0002-7884-6861]en
Appears in Collections:Medicine publications

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