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O-GlcNAcylation is a post-translational modification catalysed by O-GlcNAc transferase (OGT). Missense mutations in OGT have been associated with developmental disorders, OGT-linked congenital disorder of glycosylation (OGT-CDG), which are characterized by intellectual disability. OGT relies on the hexosamine biosynthetic pathway (HBP) for provision of its UDP-GlcNAc donor. We considered whether mutations in UDP-N-acetylhexosamine pyrophosphorylase (UAP1), which catalyses the final step in the HBP, would phenocopy OGT-CDG mutations. A de novo mutation in UAP1 (NM_001324114:c.G685A:p.A229T) was reported in a patient with intellectual disability. We show that this mutation is pathogenic and decreases the stability and activity of the UAP1 isoform AGX1 in vitro. X-ray crystallography reveals a structural shift proximal to the mutation, leading to a conformational change of the N-terminal domain. These data suggest that the UAP1 A229T missense mutation could be a contributory factor to the patient phenotype.
- enzyme mutation
- protein structure
Investigating the role of UDP-N-acetylhexosamine pyrophosphorylases in regulating O-GlcNAcylation in human diseaseAuthor: Chen, X., 2021
Supervisor: van Aalten, D. (Supervisor)
Student thesis: Doctoral Thesis › Doctor of Philosophy