The O-GlcNAc Transferase Intellectual Disability Mutation L254F Distorts the TPR Helix

Summary O -linked β- N -acetyl- D -glucosamine ( O -GlcNAc) transferase (OGT) regulates protein O -GlcNAcylation, an essential post-translational modification that is abundant in the brain. Recently, OGT mutations have been associated with intellectual disability, although it is not understood how they affect OGT structure and function. Using a multi-disciplinary approach we show that the L254F OGT mutation leads to conformational changes of the tetratricopeptide repeats and reduced activity, revealing the molecular mechanisms contributing to pathogenesis.