期刊
FEBS LETTERS
卷 594, 期 4, 页码 717-727出版社
WILEY
DOI: 10.1002/1873-3468.13640
关键词
intellectual disability; neurodevelopment; O-GlcNAc; OGlcNAC transferase; OGT; XLID
资金
- Wellcome Trust Investigator Award [110061]
- NIH [T32GM007748]
- SPRINT/MND-MS Scholarship (University of Edinburgh)
- Estonian Research Council [PRG471, PUTJD827]
- National Human Genome Research Institute [UM1 HG008900]
- National Heart, Lung, and Blood Institute under the TransOmics for Precision Medicine (TOPMed) programme
- National Eye Institute
- Research Ethics Committee of the University of Tartu [263/M-16]
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.
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