University of Dundee

MRC DTP iCASE: Using artificial intelligence to identify and dissect candidate conveyors of OGT-linked intellectual disability

Extended  closing date for this project now 30.05.21

Applications for this round of recruitment are open to candidates who meet the following eligibility criteria –

  • Be a UK National (meeting residency requirements), or
  • Have settled status, or
  • Have pre-settled status (meeting residency requirements), or
  • Have indefinite leave to remain or enter

Further information on eligibility and residency requirements can be found in the UKRI Training Grant Terms & Conditions (found here: https://www.ukri.org/wp-content/uploads/2021/03/UKRI-150321-TrainingGrantsTermsConditions-Mar2021.pdf) and accompanying guidance documentation (found here: https://www.ukri.org/wp-content/uploads/2020/10/UKRI-291020-guidance-to-...)

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). OGT catalyses O-GlcNAcylation and possesses a catalytic domain and N-terminal tetratricopeptide repeats (TPRs) that mediate substrate recognition.

Very recently, the van Aalten lab has reported families where missense OGT mutations segregate with intellectual disability (Pravata et al., 2019). In a collaborative study we have shown that in addition to intellectual disability, these patients share clinical phenotypes including developmental delay, behavioural problems, ataxia, clinodactyly and microcephaly (Pravata et al., 2020). This suggests a new syndrome that we have named OGT-linked  Congenital Disorder of Glycosylation (OGT-CDG) (Pravata et al., 2020). Many of the OGT-CDG patients possess mutations in the active site of OGT that disrupt substrate binding/catalytic activity, O-GlcNAc homeostasis and Oga/Ogt expression in mouse embryonic stem cells (mESCs) and Drosophila. The central hypothesis of this proposal 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 ID.

The challenge now is to, from the >4000 known O-GlcNAc proteins, identify “the” candidate conveyors of the OGT-CDG phenotypes – and this project aims to do this using novel AI technology developed by the industrial partner Ex Scientia.

There are two aims that can run in parallel due to availability of significant preliminary data:

AIM 1: Identification of candidate conveyors of the OGT-CDG phenotypes. Using novel AI technology at Ex Scientia, an engine trained on literature data will be used to extract candidate O-GlcNAc proteins that are strongly associated with similar phenotypes as observed in OGT-CDG.

AIM 2: Dissecting biological and molecular mechanisms linking O-GlcNAc sites to OGT-CDG phenotypes. We will dissect the biological functions and molecular consequences of site-specific O-GlcNAcylation on OGT-CDG candidate proteins, using model systems (mESCs/Drosophila) already established in the van Aalten lab. This includes a new method to site-specifically increase O-GlcNAc stoichiometry in vivo.

 

References

Pravata, V. M., Muha, V., Gundogdu, M., Ferenbach, A. T., Kakade, P. S., Vandadi, V., … van Aalten, D. M. F. (2019). Catalytic deficiency of O-GlcNAc transferase leads to X-linked intellectual disability. Proceedings of the National Academy of Sciences of the United States of America, 116(30), 14961–14970. https://doi.org/10.1073/pnas.1900065116

Pravata, V. M., Omelková, M., Stavridis, M. P., Desbiens, C. M., Stephen, H. M., Lefeber, D. J., … van Aalten, D. M. F. (2020). An intellectual disability syndrome with single-nucleotide variants in O-GlcNAc transferase. European Journal of Human Genetics. https://doi.org/10.1038/s41431-020-0589-9

Eligibility