A missense mutation in the catalytic domain of O-GlcNAc transferase links perturbations in protein O-GlcNAcylation to X-linked intellectual disability.

Veronica M Pravata, Mehmet Gundogdu, Sergio G Bartual, Andrew T Ferenbach, Marios Stavridis, Katrin Õunap, Sander Pajusalu, Riina Žordania, Monica H Wojcik, Daan M F van Aalten

FEBS letters 2020 Feb

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X-linked intellectual disabilities (XLID) are common developmental disorders. The enzyme O-GlcNAc transferase encoded by OGT, a recently discovered XLID gene, attaches O-GlcNAc to nuclear and cytoplasmic proteins. As few missense mutations have been described, it is unclear what the aetiology of the patient phenotypes is. Here, we report the discovery of a missense mutation in the catalytic domain of OGT in an XLID patient. X-ray crystallography reveals that this variant leads to structural rearrangements in the catalytic domain. The mutation reduces in vitro OGT activity on substrate peptides/protein. Mouse embryonic stem cells carrying the mutation reveal reduced O-GlcNAcase (OGA) and global O-GlcNAc levels. These data suggest a direct link between changes in the O-GlcNAcome and intellectual disability observed in patients carrying OGT mutations. © 2019 The Authors. FEBS Letters published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.

Citation

Veronica M Pravata, Mehmet Gundogdu, Sergio G Bartual, Andrew T Ferenbach, Marios Stavridis, Katrin Õunap, Sander Pajusalu, Riina Žordania, Monica H Wojcik, Daan M F van Aalten. A missense mutation in the catalytic domain of O-GlcNAc transferase links perturbations in protein O-GlcNAcylation to X-linked intellectual disability. FEBS letters. 2020 Feb;594(4):717-727