Mechanistic analysis of neurodevelopmental disorders caused by mutations in the gene RAC1

About the Project

RAC1 is a signalling protein that regulates many cellular processes and is essential during embryonic development. We recently discovered a novel genetic diseasecalled RAC1-related neurodevelopmental disorder (RAC1-NDD) that results from mutations in the RAC1 gene. Individuals with this condition have a variety of neurological abnormalities, but the nature of abnormalities differ between individuals with different mutations. This project will explore the molecular and cellular mechanisms by which the RAC1 mutations identified in patients give rise to neurological abnormalities and why different mutations in the RAC1 gene result in different abnormalities. This will be done using a combination of cell culture and model organism approaches. Cell culture will be used to explore how different RAC1 mutations affect cell morphology and behaviour. The fruit fly Drosophila will be used as a simple animal model to investigate how RAC1 mutations affect neuronal development and function. We then plan to use the frog Xenopus to model the effect of selected RAC1 mutations on vertebrate brain development. In addition, computational bioinformatic approaches will be used to identify and characterise novel disease mutations in RAC1 and related genes.

This is a truly inter-disciplinary project led by basic scientists and a clinical academic who will bring complementary areas of expertise. The project will equip the student with a range of versatile skills including bioinformatic analysis of human genome/exome sequences, cell culture, modelling human disease in model organisms and cloning/transgenesis techniques such as CRISPR. The skills and knowledge provided by project will provide a solid foundation for a future career in disease-gene discovery, precision medicine, translational medicine or neuroscience.

Eligibility

Applicants must have obtained or be about to obtain a minimum Upper Second class UK honours degree, or the equivalent qualifications gained outside the UK, in a relevant discipline.

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 Neuroscience 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 2 med fee. Details of our different fee bands can be found on our website View Website

References

Banka S, Bennington A, Baker MJ, Rijckmans E, Clemente GD, Ansor NM, Sito H, Prasad P, Anyane-Yeboa K, Badalato L, Dimitrov B, Fitzpatrick D, Hurst ACE, Jansen AC, Kelly MA, Krantz I, Rieubland C, Ross M, Rudy NL, Sanz J, Stouffs K, Xu ZL, Malliri A, Kazanietz MG, Millard TH. Activating RAC1 variants in the switch II region cause a developmental syndrome and alter neuronal morphology. Brain (2022) 145, 4232-4245. doi: 10.1093/brain/awac049. PMID: 35139179

Reijnders MRF, Ansor NM, Kousi M, Yue WW, Tan PL, Clarkson K, Clayton-Smith J, Corning K, Jones JR, Lam WWK, Mancini GMS, Marcelis C, Mohammed S, Pfundt R, Roifman M, Cohn R, Chitayat D; Deciphering Developmental Disorders Study, Millard TH, Katsanis N, Brunner HG, Banka S. RAC1 Missense Mutations in Developmental Disorders with Diverse Phenotypes. Am. J. Hum. Genet. (2017) 101 466-477.