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

TY - JOUR

T1 - A missense mutation in the catalytic domain of O-GlcNAc transferase links perturbations in protein O-GlcNAcylation to X-linked intellectual disability

AU - Pravata, Veronica M.

AU - Gundogdu, Mehmet

AU - Bartual, Sergio G.

AU - Ferenbach, Andrew T.

AU - Stavridis, Marios

AU - Õunap, Katrin

AU - Pajusalu, Sander

AU - Žordania, Riina

AU - Wojcik, Monica H.

AU - van Aalten, Daan M. F.

N1 - © 2019 The Authors. FEBS Letters published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.

PY - 2019/11/7

Y1 - 2019/11/7

N2 - 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.

AB - 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.

KW - O-GlcNAc

KW - OGT

KW - OGlcNAC transferase

KW - XLID

KW - intellectual disability

KW - neurodevelopment

UR - https://www.scopus.com/pages/publications/85075126533

U2 - 10.1002/1873-3468.13640

DO - 10.1002/1873-3468.13640

M3 - Article

C2 - 31627256

SN - 0014-5793

VL - 594

SP - 717

EP - 727

JO - FEBS Letters

JF - FEBS Letters

IS - 4

ER -