Daan van Aalten, Aarhus University, Denmark

Biography

Daan van Aalten is Professor at Aarhus University, Denmark. Originally graduated as a chemist (1994) followed by a biocomputing PhD (1997), Daan has been working on the interface between cell signalling and glycobiology since joining Dundee as a PI (1999) using a multidisciplinary approach covering the spectrum from synthetic chemistry to genetics. Daan’s work in O-GlcNAc field has included development of chemical biology tools, uncovering novel molecular/biological mechanisms and development of animal models. Following a recent move to Aarhus university his lab now focuses on the dissection of an O-GlcNAc transferase intellectual disability syndrome.

Abstract 

The O-GlcNAc post-translational modification of intracellular proteins is essential for embryogenesis, development and brain function. Our knowledge of how O-GlcNAcylation regulates protein function and associated pathways is limited. An exciting new inroad into this is our recent discovery that patients with mutations in O-GlcNAc transferase (OGT) suffer from intellectual disability and (neuro)developmental delay (e.g. PNAS 2019), in a syndrome that we have defined as OGT-Congenital Disorder of Glycosylation (OGT-CDG, Eur.J.Hum.Gen. 2020). Although several OGT-CDG mutations have now been reported, it is not understood how these mutations are mechanistically linked to the neuro-developmental deficits seen in the patients.

I will describe common symptoms (intellectual disability, epilepsy, developmental delay) in a cohort of >65 unpublished patients, and will present the first example of genome editing in mice to generate three independent lines that carry OGT-CDG mutations. Excitingly, these mouse are viable, unlike previously reported Ogt knock-out mice, allowing the first phenotypic characterization of a vertebrate model of OGT-CDG. Notably, these mice show changes in size and weight suggesting developmental delay as observed in patients. Additionally, we observe changes in O-GlcNAc homeostasis to compensate for loss of OGT catalytic activity in the brain. This is associated with microcephaly, behavioural and cognitive defects, including hyperactivity, anxiety, compulsive behaviour and altered spatial working memory – again recapitulating several of the symptoms in OGT-CDG patients. Unpublished work on mechanistic insights and avenues for treatment of this syndrome will be shared.