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

AbstractX ‐linked Intellectual Disabilities (XLID) are common developmental disorders. The enzymeO‐GlcNAc transferase encoded byOGT, a recently discovered XLID gene, attachesO‐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 th is variant leads to structural rearrangements in the catalytic domain. The mutation reducesin vitro OGT activity on substrate peptides/protein. Mouse embryonic stem cells carrying the mutation reveal reducedO‐GlcNAcase (OGA) and globalO‐GlcNAc levels. These data suggest a direct link between changes in theO‐GlcNAcome and intellectual disability observed in patients carrying OGT mutations.

Source: FEBS Letters - October 17, 2019 Category: Biochemistry Authors: 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 Tags: RESEARCH LETTER Source Type: research