Investigating neurodevelopmental disorders caused by defects in the protein synthesis machinery

Division of Neuroscience, The University of Manchester

Dr P Kasher

Prof Siddharth Banka

Prof Graham Pavitt

Applications accepted all year round

Self-Funded PhD Students Only

About the Project

Background:

Translation of mRNA into proteins is a critical cellular process for normal development and function. An increasing number of genetic disorders caused by variants in genes encoding translation factors are now known. We recently described a novel human disorder called Faundes-Banka Syndrome (OMIM #619376) caused by mutations in the translation factor EIF5A1 gene resulting in developmental problems, small head size and craniofacial defects in children. Using yeast and zebrafish model systems we showed how EIF5A1 mutations lead to impaired eIF5A function and cause phenotypes consistent with the human disorder. Interestingly, in the same model systems we have shown that a specific food supplement (spermidine) may be a potential treatment for this disease. We have now also found patients with related neurodevelopmental disorders that have mutations in other related translation factor genes.

Project:

This project aims to improve diagnosis, mechanistic understanding and treatment of one or more neurodevelopmental disorder caused by defects in the protein synthesis machinery by –

1. Computationally Investigating the landscape of variants in genes encoding members of protein synthesis machinery in large whole exome or genome datasets from healthy and disease populations to Identify novel genetic variants and/or disorders.
2. Investigate functional impact of selected novel variants by developing a whole animal model (zebrafish), using CRISPR, combined with neurodevelopmental phenotypic and biochemical characterisation via fluorescent microscopy, RNA-seq, mass spectrometry and biochemical assays of global and specific protein synthesis functions.
3. Investigate treatment in neurodevelopmental disease zebrafish models caused by variants in protein synthesis genes using pharmacological and genetic approaches.

Outcome:

The student will contribute to providing novel insights into a human disorder at the interface of fundamental biology and translational precision medicine. The student will learn several fundamental interdisciplinary and quantitative skills, as well as gaining significant experience of studying whole organism physiology in context of human disease

Candidates are expected to hold (or be about to obtain) a minimum 2:1 Bachelors Degree with Honours (or equivalent) in a related area/subject. Candidates with experience in zebrafish modelling or with an interest in neurodevelopmental disease and genetics are encouraged to apply.

Before you Apply

Applicants must make direct contact with preferred supervisors before applying. It is your responsibility to make arrangements to meet with potential supervisors, prior to submitting a formal online application.

How to Apply

To be considered for this project you MUST submit a formal online application form – on the application form select PhD Medical Genetics Programme. Full details on how to apply can be found on the Website: How to apply for postgraduate research at The University of Manchester

If you have any queries regarding making an application please contact our admissions team FBMH.doctoralacademy.admissions@manchester.ac.uk

Equality, Diversity and Inclusion

Equality, diversity and inclusion is fundamental to the success of The University of Manchester, and is at the heart of all of our activities. The full Equality, diversity and inclusion statement can be found on the website: Equality, diversity and inclusion (EDI | Postgraduate Research | Biology, Medicine and Health | University of Manchester)

Funding Notes

Applications are invited from self-funded students. This project has a Band 3 (high) fee. Details of our different fee bands can be found on our website View Website

References

1. Park MH, Kar RK, Banka S, Ziegler A, Chung WK. (2021) Post-translational formation of hypusine in eIF5A: implications in human neurodevelopment. Amino Acids. doi: 10.1007/s00726-021-03023-6
2. V Faundes, MD Jennings, S Crilly, S Legraie, S Cuvertino, SJ Davies, A Douglas, A Fry, V Harrison, J Amiel, D Lehalle, WG Newman, P Newkirk, J Ranells, M Splitt, The Deciphering Developmental Disorders (DDD) Study, CT Gordon, PR Kasher*, GD Pavitt*, S Banka* (2021). Impaired eIF5A function causes a Mendelian disorder that is partially rescued in model systems by spermidine. Nature Communications 12:833. doi: 10.1038/s41467-021-21053-2.