About the Project
CASK is a highly conserved, multi-domain scaffolding protein that plays essential roles in synaptic development, neuronal communication, and brain formation. It coordinates the assembly of large protein complexes containing interaction partners such as neurexins, syndecans, and ion channels, which are critical for establishing and maintaining functional neural circuits. Disruption of these molecular networks can have profound consequences for nervous system development and function. Pathogenic…
variants in CASK are associated with a spectrum of severe X linked neurodevelopmental disorders, including X-linked intellectual developmental disorder (XLID), with or without nystagmus and FG syndrome (OMIM: 300422), X-linked optic and ophthalmic problems, and intellectual developmental disorder and microcephaly with pontine and cerebellar hypoplasia (MICPCH) (OMIM: 300749). Disease causing variants include loss-of-function mutations, splice-site alterations, and missense changes that can reduce CASK abundance, impair protein interactions, and disrupt the assembly of synaptic signalling complexes. Despite growing clinical recognition of CASK-associated disorders, the molecular mechanisms underlying many disease-causing variants remain poorly understood.
This interdisciplinary PhD project will combine artificial intelligence, structural biology, genetics, and functional genomics to investigate how pathogenic mutations alter CASK structure and function. Working with Drs Robin Corey and Amber Knapp-Wilson, the student will apply state of-the-art AI-driven molecular modelling tools, including AlphaFold3, together with advanced structural bioinformatics approaches to predict the effects of disease-associated variants on protein stability, dynamics, and molecular interactions. These analyses will form the basis of a variant-prioritisation framework designed to identify mutations most likely to have significant functional consequences.
The highest-priority variants will then be tested experimentally. In Prof Hodge’s laboratory, the student will introduce selected mutations into Drosophila models and assess their effects on behaviour and neurological function. In collaboration with Prof Ben Housden, they will use functional genomics approaches to determine how CASK dysfunction alters gene expression and cellular pathways. Together, these studies will provide mechanistic insight into how molecular defects propagate to changes in cells, tissues, and whole-organism phenotypes.
A further objective of the project is to identify previously unrecognised functional regions within CASK that may represent novel therapeutic targets. By integrating structural modelling, evolutionary analysis, protein dynamics, and ligand-binding site prediction, the student will investigate whether CASK contains cryptic or allosteric pockets that could be exploited pharmacologically. These analyses will generate new hypotheses and provide a foundation for future drug-discovery efforts targeting CASK-associated disorders.
The project offers extensive training in computational structural biology, artificial intelligence, bioinformatics, genetics, molecular biology, and quantitative data analysis. Students will gain experience working across both computational and experimental research environments, developing highly transferable skills that are increasingly sought after in academia and industry.
Importantly, the student will play an active role in shaping the project’s direction. They will help determine which variants and biological mechanisms should be prioritised for experimental investigation and will be encouraged to pursue new questions emerging from their findings such as investigating potential therapeutic targets, or developing improved methods for predicting the impact of disease-causing variants. This flexibility provides an opportunity to make original scientific contributions while advancing our understanding of rare but devastating neurodevelopmental disorders and informing future therapeutic strategies.
How to Apply
A list of all the projects and how to apply is available on the GW4 BioMed website at gw4biomed.ac.uk. You may select up to 2 projects and submit one application per candidate only.
Please complete an application to the GW4 BioMed3 for an ‘offer of funding’. If successful, you will also need to make an application for an 'offer to study' to your chosen institution later.
Please complete the online application form linked from our website by 5.00pm on Wednesday, 21st October 2026. Please note that we may close the application process before the stated deadline if an unprecedented number of applications are received– check the GW4 BioMed website for details and updates. If you are shortlisted for interview, you will be notified from Tuesday, 22nd December 2026. Interviews will be held virtually on 26th and 27th January 2027. Studentships will start on 1st October 2027.
Further Information
For informal enquiries, please contact GW4BioMed@cardiff.ac.uk
For project related queries, please contact the respective supervisors listed on the project descriptions on the GW4 BioMed website.
Funding Notes
These studentships are funded through GW4 BioMed3 MRC Doctoral Landscape Programme and consist of UK tuition fees, as well as a Doctoral Stipend matching UK Research Council National Minimum (£21, 805 p.a. for 2026/27, updated each year).
Additional research training and support funding of up to £5,000 per annum is also available.
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