Primary Immunodeficiencies: molecular genetics and the underlying biological mechanisms of disease

Project description

The majority of patients currently managed by clinical immunology have rare disorders; however, within this group there are many who do not have a clear diagnosis. Some of these patients have demonstrable abnormalities of the immune system which can be life-threatening or cause significant morbidity, but which do not fit any diagnostic criteria. Even within the group of patients who do have a recognised diagnosis of primary immunodeficiency (PID), this diagnosis is frequently a clinical one without full understanding of the molecular basis of the condition. This results in difficulties selecting the correct treatment options or advising patients about their long-term outcome.

We have used next-generation sequencing technology for the diagnosis of complex patients presenting to paediatric and adult immunology clinics. In selected cases, this has led to the rapid diagnosis and improved clinical decision making. Currently we have several families who are being screened for novel monogenic disorders.The aim of this project is to understand the functional consequences of some of the important novel genetic mutations we have identified to date, and to explore the underlying molecular mechanisms responsible for disease in the remaining families. Pathogenic mutations in candidate genes will be assessed as appropriate, by

  • Segregation with disease and frequencies in ethnically matched controls
  • Molecular modelling of mutations
  • Effects on splicing patterns and products in vivo
  • Expression patterns, both at the mRNA and protein level in vivo
  • Targeted genome editing using CRISPR technology to study gene function
  • Recombinant protein expression
  • Depending on the proposed function of the disease associated protein, additional methods such as immunofluorescence microscopy, flow cytometry, siRNA/shRNA gene knockdown will be used to further explore the consequences of the mutation(s)

The student will be based in the section of Translational Medicine (TMED), School of Medicine, University of Leeds. This project will provide research training in a wide range of molecular and cell biology techniques.


  1. Bigley V, et al. (2017). Bi-allelic IRF8 mutation: a complex immunodeficiency syndrome with dendritic cell deficiency, monocytopenia and immune dysregulation. J Allergy Clin Immunol.
  2. Lawless D, et al. (2017). Biallelic mutations in tetratricopeptide repeat domain 7A (TTC7A) cause common variable immunodeficiency-like phenotype with enteropathy. J Clin Immun 37(7):617–622.
  3. Mistry A, et al. (2017). Glucose-6-Phosphatase Catalytic Subunit 3 (G6PC3) deficiency associated with autoinflammatory complications Front Immunol. | doi: 10.3389/fimmu.2017.01485

Entry requirements

This project is available immediately to both Home/EU rate applicants and International applicants who are able to self-fund their studies. Students must be able to provide the appropriate level of fees based on their fee status plus laboratory consumables costs per year. This is in addition to the provision of personal living expenses.

You should hold a first degree equivalent to at least a UK upper second class honours degree in a relevant subject.

Candidates whose first language is not English must provide evidence that their English language is sufficient to meet the specific demands of their study, the Faculty minimum requirements are

  • British Council IELTS - score of 6.5 overall, with no element less than 6.0
  • TOEFL iBT - overall score of 92 with the listening and reading element no less than 21, writing element no less than 22 and the speaking element no less than 23.

Applicants with sufficient funding must still undergo formal interview prior to acceptance in order to demonstrate scientific aptitude and English language capability.

How to apply

To apply for this position potential applicants should initially contact the lead supervisor, Dr Frederique Ponchel directly.

Following this, please submit a formal application by completing a Faculty Application form and send this alongside a full academic CV, degree transcripts (or marks so far if still studying) and degree certificates to the Faculty Graduate School.

We also require 2 academic references to support your application. Please ask your referees to send these references on your behalf, directly by email.

If you have already applied for other positions, or any scholarships, using the Faculty Scholarship Application form you do not need to complete this form again. Instead you should email to inform us you would like to be considered for this scholarship project.