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

TitleA missense mutation in the catalytic domain of O-GlcNAc transferase links perturbations in protein O-GlcNAcylation to X-linked intellectual disability.
Publication TypeJournal Article
Year of Publication2020
AuthorsPravata, VM, Gundogdu, M, Bartual, SG, Ferenbach, AT, Stavridis, M, Õunap, K, Pajusalu, S, Žordania, R, Wojcik, MH, van Aalten, DMF
JournalFEBS Lett
Volume594
Issue4
Pagination717-727
Date Published2020 Feb
ISSN1873-3468
Abstract

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.

DOI10.1002/1873-3468.13640
Alternate JournalFEBS Lett.
PubMed ID31627256
PubMed Central IDPMC7042088
Grant List / WT / Wellcome Trust / United Kingdom
T32 GM007748 / GM / NIGMS NIH HHS / United States
UM1 HG008900 / HG / NHGRI NIH HHS / United States
110061 / WT / Wellcome Trust / United Kingdom