Pleiotropic disorders of mitochondrial translation

Lead Research Organisation: University of Manchester
Department Name: School of Biological Sciences


Many rare conditions are caused by changes in genes required for biological processes essential for normal human health. Hearing loss and infertility are two important common health problems that can be caused by genetic changes. Studying the causes of rare conditions is important for the affected individuals and their families, but often helps us to understand why people are affected by more common conditions. Therefore, our research will focus on a very rare condition called Perrault Syndrome, which causes severe hearing loss in both males and females, problems with fertility in females, and debilitating nerve problems in about half of affected individuals. While Perrault syndrome is rare, it is under-diagnosed, especially in men or in girls before puberty. Perrault syndrome can also be a far more severe condition, which can be fatal in early childhood. Over the past 10 years we, and others, have found that changes in seven genes can cause the condition. The genes that cause Perrault syndrome are required for the function of the mitochondria, a structure within a cell that produces energy and is very important for human health.
Our recent research has discovered six new genes not previously known to cause this condition.

We will carry out a programme of research, building on our recent discoveries of why the changes in these six new genes result in this condition. Importantly, three of these genes have never been shown to act in mitochondria, so our studies will provide completely new information as to how this condition can come about. In patients where we have not yet found the cause we will use a new technique to look at all of the DNA in a cell called whole genome sequencing to provide these families with an explanation and understand the biology of this condition.

We have assembled an expert team linked with collaborators around the world to support these studies.
We have already collected genetic samples and information from families affected by Perrault Syndrome who do not have changes in the genes that we already know cause the condition. We will study in depth the new genes that we have discovered and see how they disrupt the workings of the mitochondria. This information will help us to understand the next steps in designing effective treatment approaches.

The applications and benefits of this work will be significant. The information we obtain will help patients and their families affected by this devastating condition by providing a more precise and rapid diagnosis, which will reduce the time it takes from when a patient is first seen to obtain a certain diagnosis and to get appropriate clinical care and reduce the need for unnecessary investigations. Our research findings will be immediately adopted into standard genetic tests provided throughout the NHS for individuals with hearing loss and infertility.

Technical Summary

Perrault syndrome (PS) is a clinically and genetically heterogeneous genetic disorder presenting with profound sensorineural hearing loss (SNHL), ovarian insufficiency, and often progressive neurological impairment. The variable onset and severity of features provides a window of opportunity for therapeutic intervention. Over the past decade we, and others, have identified biallelic hypomorphic variants in 7 genes that definitively cause PS. These genes almost exclusively affect protein translation in the mitochondria. Importantly, we have discovered, more deleterious variants in PS-associated genes result in early-onset, often fatal, multi-system disorders, with neurodevelopmental delay and lactic acidosis, consistent with mitochondrial dysfunction.

Our recent studies of families affected by PS have identified variants in 6 additional genes, including individuals ascertained through the 100,000 Genomes Project. Three of these new PS genes have not previously been linked to mitochondrial translation, whereas the other three are key to this process. This proposal provides a unique opportunity to determine the molecular mechanisms resulting in this pleiotropic clinical disorder and how these mechanisms can be exploited for therapeutic control.

We specifically aim to i) undertake functional studies to define the effects of variants in three novel disease associated genes, DAP3, MRPL49 and ERAL1; ii) undertake studies to define how NOP14 and GPN2 result in disease through mitochondrial dysfunction; iii) determine whether altered prenylation through DAP3 results in mitochondrial disease; and iv) identify additional genes associated with PS.


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Kaiyrzhanov R (2022) Phenotypic continuum of NFU1 -related disorders in Annals of Clinical and Translational Neurology

Description Biochemical characterisation of CLPP 
Organisation University of Toronto
Country Canada 
Sector Academic/University 
PI Contribution Characterisation of cells with CLPP variants - immunohistochemistry
Collaborator Contribution Biochemical characterisation. of disease associated CLPP variants - proposing potential therapeutic rescue
Impact Nil yet - in progress
Start Year 2021
Description Columbia - Perrault 
Organisation Columbia University
Country United States 
Sector Academic/University 
PI Contribution Sharing of data about new genes that result in hearing loss. We will design lab assays that will provide evidence of the link between the new genes and Perrault syndrome.
Collaborator Contribution Sharing data about gene variants and clinical data for novel genes associated with Perrault syndrome.
Impact No outputs have been generated yet but we have shared data and information relating to the discovery of two new genes that resulting hearing loss (Perrault syndrome)
Start Year 2021
Description Discovery and characterisation in Perrault syndrome 
Organisation University of Melbourne
Country Australia 
Sector Academic/University 
PI Contribution Sharing information on novel disease gene discoveries - plans for joint funding
Collaborator Contribution Sharing information on novel disease gene discoveries - plans for joint funding
Impact Nil yet - in progress - future applications/funding
Start Year 2022