Intellectual disability and neurogenesis defects associated with increased turnover of an O-GlcNAcase variant

Abstract

AbstractIntellectual Disability (ID) is characterised by substantial limitations in cognitive function and adaptive behaviour, affecting 1-3% of the population. Protein O-GlcNAcylation is a posttranslational modification of nucleocytoplasmic proteins regulated by two opposing enzymes: O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA). Recently, missense mutations inOGThave been shown to segregate with ID, associated with compensatory reduction of OGA expression, although it is unclear whether this is mechanistically linked to the disease. Here, we report a patient with a K885Nde novomissense mutation in the C-terminal pseudo histone acetyltransferase domain of OGA, associated with ID, infantile spasms and autism. While the K885N mutation does not affect protein stability or activityin vitro, this residue sits in the canonical GCN5 acetyltransferase family acceptor binding cleft. Strikingly, mouse embryonic stem cells edited to harbour the K885N mutation show increased OGA turnover and defects in neurogenesis. Taken together, these data suggest a link between missense mutations in OGA and ID.