University of Dundee

CSC - Intellectual disability in patients with mutations in O-GlcNAc transferase

Intellectual disability (ID) and associated developmental delay are severe neurodevelopmental conditions that affect approximately 1% of the world population. 5% -10% of ID cases are due to mutations in genes located on the X chromosome. One of the genes shown to co-segregate with X-linked intellectual disability (XLID) in twelve patients is the gene ogt. Ogt encodes an essential enzyme, the O-GlcNAc transferase, which catalyses an abundant nucleocytoplasmic post-transcriptional modification O-GlcNAcylation. We have recently described this as a novel syndromic form of XLID (“OGT-XLID”) and are now pursuing four possible hypotheses for underpinning biological mechanisms, potentially revealing possible future targets for treatment. In your project you could, depending on your interests, interact with clinicians who have found novel OGT mutations from exsome sequencing and use, depending on your interests, a number of possible techniques to study the effects of these mutations. This ranges from biochemical, molecular, cell biological to genetic techniques in model systems ranging from in vitro biophysical/chemistry approaches to genetic approaches in stem cells, flies and mice. You will receive expert supervision within the context of an established and well-funded lab. There may be chances for you to interact with our satellite lab at Xiangya Hospital in Changsha. We would aim for your experiments to form the basis of several high quality scientific publications, as has been the case for the 22 PhD students that have passed through the lab so far. We are looking for hard working, self-driven and independently thinking students. Contact me for an informal chat on dmfvanaalten@dundee.ac.uk

Three recent relevant publications:

N. Selvan, R. Williamson, D. Mariappa, D.G. Campbell, R. Gourlay, A.T. Ferenbach, T. Aristotelous, I. Hopkins-Navratilova, M. Trost and D.M.F. van Aalten, "A mutant O-GlcNAcase enriches Drosophila developmental regulators", Nature Chem.Biol. (2017), 13, 882-887.

M. Gundogdu, S. Llabrés, A. Gorelik, A.T. Ferenbach, U. Zachariae and D.M.F. van Aalten, "The O-GlcNAc transferase intellectual disability mutation L254F distorts the TPR helix", Cell Chem.Biol. (2018), 25, 513-518.

V.M. Pravata, V. Muha, M. Gundogdu, A.T. Ferenbach, P. Kakade, V. Vandadi, A.C. Wilmes, V.S. Borodkin, S. Joss, M.P. Stavridis and D.M.F. van Aalten, "O-GlcNAc transferase catalytic deficiency in twins with X-linked intellectual disability", Proc.Natl.Acad.Sci.USA, (2019), 116, 14961-14970.