Aarhus University Seal

Daan van Aalten

Defects in protein O-GlcNAcylation and intellectual disability

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. 

News


DANDRITE Annual Report of 2024

- Policy and strategy

2024 was a year of transitions, major milestones, and accelerating momentum at DANDRITE. Discover the breakthroughs, the people behind them, and the…

1.934.673 steps, one winner and a week full of Spring

A glimpse from the week. From top left: Silent Fit in the University Parc. Bottom right: the walking team. Bottom left and top right: Spring Party themed: The Mad Scientist's Tea Party.
- Events

From 12–16 May, the DANDRITE Community marked the arrival of spring in Denmark with a week of outdoor events designed to build community and celebrate…

New student in Jensen Lab

- People news

Søren Skjold Jensen is a bachelor's student at Aarhus University. As part of the preparation for his bachelor's project in the spring of 2026, he is…