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  O-GlcNAc transferase missense mutations linked to X-linked intellectual disability deregulate genes involved in cell fate determination and signaling

Selvan, N., George, S., Serajee, F. J., Shaw, M., Hobson, L., Kalscheuer, V., et al. (2018). O-GlcNAc transferase missense mutations linked to X-linked intellectual disability deregulate genes involved in cell fate determination and signaling. Journal of Biological Chemistry, 293(27), 10810-10824. doi:10.1074/jbc.RA118.002583.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0002-0DDB-A Version Permalink: http://hdl.handle.net/21.11116/0000-0002-0DDC-9
Genre: Journal Article

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 Creators:
Selvan, Nithya , Author
George, Stephan , Author
Serajee, Fatema J. , Author
Shaw, Marie, Author
Hobson, Lynne , Author
Kalscheuer, Vera1, Author              
Nripesh, Prasad, Author
Levy, Shawn E. , Author
Taylor, Juliet, Author
Aftimos, Salim, Author
Schwartz, Charles E. , Author
Huq, Ahm M. , Author
Gecz, Jozef , Author
Wells, Lance , Author
Affiliations:
1Chromosome Rearrangements and Disease (Vera Kalscheuer), Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_2385702              

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Free keywords: RNA-seq; XLID; enzyme kinetics; genetic disease; glycosyltransferase; O-linked N-acetylglucosamine (O-GlcNAc) transferase (OGT); O-linked N-acetylglucosamine (O-GlcNAc); intellectual disability; post-translational modification; transcriptomics
 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 O-GlcNAc hydrolase 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 liver X receptor/retinoid X receptor signaling, which has been implicated in neuronal development. Thus, here we reveal two 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.

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Language(s): eng - English
 Dates: 2018-05-162018-07-06
 Publication Status: Published in print
 Pages: -
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 Table of Contents: -
 Rev. Method: -
 Identifiers: DOI: 10.1074/jbc.RA118.002583
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Title: Journal of Biological Chemistry
  Other : J. Biol. Chem.
Source Genre: Journal
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Publ. Info: Baltimore, etc. : American Society for Biochemistry and Molecular Biology [etc.]
Pages: 15 Volume / Issue: 293 (27) Sequence Number: - Start / End Page: 10810 - 10824 Identifier: ISSN: 0021-9258
CoNE: /journals/resource/954925410826