In this project, Thomas Smith in Professor William Newman’s lab at the University of Manchester explores the genetic causes of Perrault syndrome, which damages mitochondria – the part of cells that produce energy – and leads to hearing loss.
Project start date: October 2021
Project end date: September 2024
About the project
Perrault syndrome is a rare inherited condition, and affected individuals have severe to profound hearing loss. Previous research has identified several genes that can result in Perrault syndrome when altered. The changes in these genes mostly lead to problems with the mitochondria, tiny structures inside cells that provide the cell with energy.
The cells we rely on for hearing require huge amounts of energy to work correctly, and so hearing is especially sensitive to problems with mitochondria. In this project, five more genes, which are important for the mitochondria, are being tested for links to Perrault syndrome
How it works
Thomas will analyse mitochondria in yeast cells and human cells containing the genetic changes identified in patients with Perrault syndrome, and look at the impact of these changes on how the mitochondria work.
He will also develop a way to measure the activity of the genes which contain these changes, to look at the impact of the specific change on the gene’s activity. This will help explain how these genetic changes lead to changes in cells that ultimately cause the hearing loss associated with Perrault syndrome.
How will this research benefit people with Perrault syndrome?
The results of this work will improve the diagnosis of Perrault syndrome and improve our understanding of how problems with mitochondria can lead to hearing loss. Understanding rare types of hearing loss, such as Perrault syndrome, may also give important insights into more common forms of hearing loss, like auditory neuropathy.
What we’ve learned so far
This work led to and contributed to the identification of two new genes called DAP3 and MRPL49 that cause Perrault syndrome, which will be added to hearing loss genetic tests in the NHS and globally and will allow quicker diagnosis and management.
The findings from this project were published in the American Journal of Human Genetics in 2025. Tom also confirmed the role of variants in the gene called PRORP in hearing loss published in the European Journal of Human Genetics in 2023 and Neurogenetics in 2026.
About the researchers
Thomas Smith is now a Postdoctoral Research Associate at the University of Manchester continuing his work on hearing loss through the genetic study of vestibular schwannomas. His PhD studentship was co-funded by RNID and The Masonic Charitable Foundation he was co-supervised by Professor William Newman and Professor Raymond O’Keefe.
I hope that this work furthers our understanding of the genetics and cellular mechanisms behind sensorineural hearing loss, as well as uncovering novel pathogenic variants implicated in Perrault syndrome. New genetic variants could then be added to gene panels, which can facilitate earlier diagnosis of Perrault syndrome and medical intervention.”
Professor William Newman is Professor of Translational Genomic Medicine in The Manchester Centre for Genomic Medicine at the University of Manchester and Honorary Consultant at Manchester University NHS Foundation Trust.
We hope that our research will make major progress in the understanding of why people are affected by Perrault syndrome and how we can potentially treat this devastating disorder. The funding from RNID has helped to do this alongside training a highly talented young researcher.”
