A missense mutation in a patient with developmental delay affects the activity and structure of the hexosamine biosynthetic pathway enzyme AGX1

FEBS Lett. 2021 Jan;595(1):110-122. doi: 10.1002/1873-3468.13968. Epub 2020 Nov 18.


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 UAP1A229T missense mutation could be a contributory factor to the patient phenotype.

Keywords: O-GlcNAcylation; enzyme mutation; neurodevelopment; pathogenesis; protein structure.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Crystallography, X-Ray
  • Developmental Disabilities / genetics*
  • Enzyme Stability
  • Galactosyltransferases / chemistry
  • Galactosyltransferases / genetics*
  • Galactosyltransferases / metabolism
  • Hexosamines / biosynthesis*
  • Humans
  • Mutation, Missense*
  • Protein Processing, Post-Translational
  • Sequence Homology, Amino Acid


  • Hexosamines
  • Galactosyltransferases
  • UDP-GalNAc pyrophosphorylase AGX1, human