Protein O-GlcNAcylation is an essential posttranslational modification of Ser/Thr residues on nucleocytoplasmic proteins with N-acetylglucosamine (GlcNAc). It is regulated by two opposing enzymes: O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA) (Fig. 1). OGT catalyses O-GlcNAcylation and possesses a catalytic domain and N-terminal tetratricopeptide repeats (TPRs) that mediate substrate recognition. Ogt is X-linked in vertebrates and is required for mouse embryogenesis and fly development. Very recently, we have reported families where missense OGT mutations segregate with intellectual disability (Fig. 1). These patients share further clinical symptoms, such as developmental delay, behavioural problems, ataxia, clinodactyly and microcephaly.
Together this has led to the definition of a new syndromic form of ID that we have named OGT-linked Congenital Disorder of Glycosylation (OGT-CDG). The central hypothesis of the lab is that altered protein O-GlcNAcylation contributes to OGT-CDG phenotypes. These hypomorphic patient mutations provide, for the first time, an unbiased starting point to ask how mutations in OGT affect (neuro)biological processes linked to intellectual disability. We will uncover the O-GlcNAc-dependent biological and molecular mechanisms that are affected in OGT-CDG and, in the longer term, use these findings to inform and develop treatment strategies.
We are generating model systems to study and modulate OGT-CDG phenotypes. We have introduced OGT-CDG patient mutations into mESCs, Drosophila (Fig. 2) and mice (Fig. 3) to quantify biochemical, cellular, structural and behavioural phenotypes, and modulate these using genetic, chemical and metabolic approaches. We are identifying candidate conveyors of the OGT-CDG phenotypes using these model systems and are dissecting biological and molecular mechanisms linking O-GlcNAc sites to OGT-CDG phenotypes.
Our lab has recently moved to the Department of Molecular Biology and Genetics (MBG) at Aarhus University with the help of a generous Laureate Grant from the Novo Nordisk Foundation and we are looking for motivated scientists at all levels to work on this question. Please write Daan (daan@mbg.au.dk) for informal enquiries.
