A missense mutation in the catalytic domain of O ‐GlcNAc transferase links perturbations in protein O ‐GlcNAcylation to X‐linked intellectual disability
| Autor: | Marios P. Stavridis, Mehmet Gundogdu, Sergio G. Bartual, Daan M. F. van Aalten, Andrew T. Ferenbach, Riina Žordania, Katrin Õunap, Veronica M. Pravata, Monica H. Wojcik, Sander Pajusalu |
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| Rok vydání: | 2019 |
| Předmět: |
Models
Molecular Glycosylation X-linked intellectual disability Mutation Missense Glycobiology Biophysics OGlcNAC transferase Biology N-Acetylglucosaminyltransferases medicine.disease_cause Biochemistry Cell Line Mice 03 medical and health sciences Structural Biology Catalytic Domain Research Letter Genetics medicine Animals Humans Transferase Missense mutation Molecular Biology Gene 030304 developmental biology chemistry.chemical_classification 0303 health sciences Mutation neurodevelopment XLID 030302 biochemistry & molecular biology Cell Biology medicine.disease Phenotype Research Letters 3. Good health Enzyme chemistry intellectual disability Cytoplasm OGT O‐GlcNAc |
| Zdroj: | Febs Letters 'FEBS Letters ', vol: 594, pages: 717-727 (2020) |
| ISSN: | 1873-3468 0014-5793 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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