A missense mutation in a patient with developmental delay that affects AGX1 activity and structure

Xiping Chen, Olawale Raimi, Andrew Ferenbach, Daan van Aalten (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

Abstract

O-GlcNAcylation is a post-translational modification catalysed by O-GlcNAc transferase (OGT). OGT missense mutations have been associated with 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), the final step in the HBP, would phenocopy OGT-CDG mutations. A de novo mutation of UAP1 (NM_001324114:c.G685A:p.A229T) was reported in a patient with intellectual disability. We show that this mutation is predicted to be pathogenic and decreases protein stability and activity 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 UAP1A229T missense mutation could be a contributory factor to the patient phenotype.
Original languageEnglish
JournalFEBS Letters
Early online date24 Oct 2020
DOIs
Publication statusE-pub ahead of print - 24 Oct 2020

Keywords

  • O-GlcNAcylation
  • enzyme mutation
  • pathogenesis
  • protein structure
  • neurodevelopment

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