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How molecular and cellular changes in mitochondrial translation cause hearing loss

Faculty of Biology, Medicine and Health

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Prof B Newman , Prof Raymond O'Keefe No more applications being accepted Funded PhD Project (UK Students Only)
Manchester United Kingdom Cell Biology Developmental Biology Genetics Neurology Neuroscience

About the Project

Perrault syndrome is a rare clinically and genetically heterogeneous autosomal recessive condition. Affected individuals have severe to profound sensorineural hearing loss. This hearing loss can be present at birth or be progressive through childhood. Affected women also have ovarian insufficiency resulting in infertility. Some individuals can be affected by white matter brain disorder (leukoencephalopathy), peripheral neuropathy and intellectual disability.

Over the past ten years our research group and others have identified many different genes that, when altered, can result in Perrault syndrome. These genes are linked to each other in that they lead to mitochondrial dysfunction. Recent work in our team has identified variants in additional genes, not previously linked to Perrault syndrome that that we believe cause this condition through mitochondrial dysfunction.

The student will :

1. use assays in yeast and patient cells to determine the function of the novel Perrault syndrome genes and confirm that they are the cause of this condition.

2. use genome and RNA sequencing to identify new genes that cause Perrault syndrome.

3. develop assays to interpret the pathogenicity of variants causing Perrault syndrome.

4. Develop strategies to understand common pathways leading to Perrault syndrome that will inform therapeutic approaches.

This work will majorly advance our understanding of this complex hearing loss disorder and provide he student will excellent foundations for a career in hearing research and human genomics.

 Entry Requirements:

Applicants are expected to hold (or about to obtain) a minimum of an upper second class undergraduate honours degree (or equivalent) in genomics/genetics. A Masters degree in a relevant subject and/or experience in a genomics laboratory or in industry is desirable. 

For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website ( Informal enquiries may be made directly to the primary supervisor. You MUST also submit an online application form - choose PhD Genomics.

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

Funding Notes

This project is funded by The Royal National Institute for Deaf People. Studentship funding is for a duration of three years to commence from 1 October 2021 and covers UK tuition fees and a stipend of £15,500 per annum. Due to funding restrictions the studentship is only open to UK nationals.


1. Demain LAM, Gerkes EH, Smith RJH, Molina-Ramirez LP, O'Keefe RT, Newman WG. A recurrent missense variant in HARS2 results in variable sensorineural hearing loss in three unrelated families. J Hum Genet. 2020 Mar;65(3):305-311.
2. Wood KA, Rowlands CF, Qureshi WMS, Thomas HB, Buczek WA, Briggs TA, Hubbard SJ, Hentges K, Newman WG, O'Keefe RT. Disease modelling of core pre-mRNA splicing factor haploinsufficiency. Hum Mol Genet. 2019;Nov 15;28(22):3704-3723
3. McDermott JH, Molina-Ramírez LP, Bruce IA, Mahaveer A, Turner M, Miele G, Body R, Mahood R, Ulph F, MacLeod R, Harvey K, Booth N, Demain LAM, Wilson P, Black GC, Morton CC, Newman WG. Diagnosing and Preventing Hearing Loss in the Genomic Age. Trends Hear. 2019 Jan-Dec;23:2331216519878983.
4. Demain LAM, Antunes D, O'Sullivan J, Bhaskhar SS, O'Keefe RT, Newman WG. A known pathogenic variant in the essential mitochondrial translation gene RMND1 causes a Perrault-like syndrome with renal defects. Clin Genet. 2018;94(2):276-277.
5. Jenkinson EM, Rehman AU, Walsh T Clayton-Smith ..King MC, Friedman TB*, Newman WG*. Perrault Syndrome is Caused by Recessive Mutations of the Mitochondrial ATP-dependent Chambered Protease CLPP. Am J Hum Genet 2013;92(4):605-13

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