PhD Studentship: Genetic modifiers to untangle disease mechanisms of RFC1 repeat expansion

PhD Studentship: Genetic modifiers to untangle disease mechanisms of RFC1 repeat expansion

University College London � Queen Square Institute of Neurology

Project: Biallelic repeat expansions in RFC1 cause Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS) and are highly prevalent in ataxia and neuropathy cases in the adult population. The clinical phenotype associated with the RFC1 repeat expansions is heterogeneous, in terms of age at onset, disease course, neurological involvement. However, determinants of the variability of RFC1 disease are still largely unknown. Furthermore, the exact mechanisms linking RFC1 repeat expansions and neurodegeneration remain elusive.
Our previous work supports a partial loss-of-function of RFC1 with tissue-specific reduced expression and impaired DNA damage response.

This proposal will focus on the investigation of genetic modifiers in RFC1 disease, leveraging the observation of naturally occurring genetic variation and controlled genome perturbation, to unravel disease relevant pathways.

We will perform a genome-wide association (GWA) analysis complemented by long read sequencing to identify genetic modifiers of onset, phenotype and progression of RFC1 disease. In parallel, we will a gene perturbation analysis using the Crispr-I technology in genetically engineered iPSC-derived sensory neurons to further investigate the effect of GWA loci and to identify additional factors which can modulate RFC1 expression and ameliorate the molecular phenotype. The results will hopefully lead to a better understanding of disease-causing mechanisms and identify potentially druggable targets.

Depending on interest, the student will have an opportunity to contribute to other projects within the team and learn a range of important techniques such as cellular, animal models, molecular biology and sequencing. The student will be expected to attend and present in local and international meetings and conferences.

The main objectives of the studentship will be:

• To carry out a GWA study, complemented with long-read sequencing of GWA significant loci, in patients with RFC1 disease to identify genetic modifiers of onset and severity
• To perform a Crispri genetic perturbation study on genetically engineered iPSC-derived neuron to identify potential druggable targets of RFC1 disease

We are looking for a highly motivated PhD student with an interest in neurodegeneration, genetics, and in the translation of basic discoveries in therapies for human neurological conditions.

Application criteria:

Essential:

• A minimum upper second-class honours degree from an undergraduate course in a biological subject or medicine
• Enthusiasm for multidisciplinary research
• Strong problem-solving skills

Desirable:

• A MSc or MRes degree
• Research experience (e.g., undergraduate project, summer internship, or industrial placement)
• Wet lab experience

How to apply:

To apply email Professor Andrea Cortese at andrea.cortese@ucl.ac.uk with a single combined pdf (labelled as: �Your Name_RFC1 PhD application� including:

• CV
• Cover letter of maximum 1 page, Arial 11, highlighting your motivation to do a PhD, particularly in the field of repeat expansions/ neurodegeneration, highlighting your future career goals after PhD
• Research Statement of maximum 1 page, Arial 11, highlighting relevant experience, expertise and interest
• Academic transcripts

Names and email addresses of 2 academic referees

Qualification Type: PhD

Location: UCL Queen Square Institute of Neurology, London WC1N 3BG

Funding amount: Fully funded with a stipend and tuition fees paid to UK level

Duration. Full-time: 3-year UCL studentship, starting from 1 October 2026.�

Funding

The post is funded by ERC Award for 3 years with PhD stipend at UCL rates and UK home PhD fees. Overseas applicants are welcome, however, they would be required to pay the international tuition fee balance.

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