Pleiotropic disorders of mitochondrial translation

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

Abstract

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.

Publications

10 25 50
 
Description Manchester NIHR Biomedical Research Centre
Amount £60,000,000 (GBP)
Funding ID NIHR203308 
Organisation National Institute for Health Research 
Sector Public
Country United Kingdom
Start 12/2022 
End 11/2027
 
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 Georg Auburger collaboration 
Organisation University Hospital, Frankfurt
Department Neuroscience Center
Country Germany 
Sector Academic/University 
PI Contribution We have discovered new disease causing genes for Perrault syndrome which aid the interpretation of the proteomic analysis made by Prof Auburger. We will share samples/data from future Perrault syndrome cases.
Collaborator Contribution Prof Auburger and his team created a CLPP knockout mouse which shares phenotypic features similar to the human phenotype of Perrault syndrome. He has characterised the mouse at a phenotypic and molecular level providing insight into how this protein is key to mitochondrial function e.g. through ribosomal assembly. Our new findings of disease causing genes in Perrault syndrome genes enhances the understanding of these data.
Impact None as yet but an agreement to share data regarding new disease gene associations so that data with mouse models can be cross referenced to provide greater understanding of mitochondrial function and dysfunction
Start Year 2017
 
Description Manipal - Anju Shukla 
Organisation Kasturba Medical College
Country India 
Sector Academic/University 
PI Contribution Characterisation of effects of novel disease gene variants with in vitro assays
Collaborator Contribution Identification of patients with variants in novel disease genes
Impact Presentation at Manipal Genetics Update VII in January 2024
Start Year 2022
 
Description Melbourne - 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
 
Description Munich - Holger Prokisch 
Organisation Helmholtz Zentrum München
Country Germany 
Sector Academic/University 
PI Contribution Undertaken characterisation of gene as part of novel disease gene discovery
Collaborator Contribution proteomic analysis of fibroblasts from patients
Impact ongoing plans for publication
Start Year 2022
 
Description Murine studies of Perrault syndrome 
Organisation Goethe University Frankfurt
Country Germany 
Sector Academic/University 
PI Contribution We identified a novel gene resulting in Perrault syndrome which informed further studies by the group in Frankfurt on their mouse model and in the understanding of mitochondrial function.
Collaborator Contribution The Frankfurt group have shared insights regarding the interacting partners of the Perrault syndrome gene.This will provide helpful information in understanding the roles of novel genes that we have identified.
Impact Nil yet
Start Year 2017
 
Description ESHG Conference 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Talk on DAP3 variants associated with Perrault syndrome by PhD student Thomas Smith
Year(s) Of Engagement Activity 2023
URL https://2023.eshg.org
 
Description Perrault syndrome talk 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Talk at rare disease conference at Crick for Rare disease day 24
Year(s) Of Engagement Activity 2024
URL https://www.crick.ac.uk/whats-on/3rd-crick-rare-diseases-conference
 
Description Poster on MRPL49 at ESHG conference 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Poster on association between variants in MRPL49 and Perrault syndrome
Year(s) Of Engagement Activity 2023
URL https://2023.eshg.org
 
Description Talk at Manchester Dysmorphology Conference 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Talk at international rare disease/genomics conference
Year(s) Of Engagement Activity 2023
URL https://www.mrcc.org.uk/news-events/manchester-dysmorphology-conference-2023/
 
Description Talk at Manipal Genetics Update VII 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Talk describing variants in DAP3, MRPL49 and GPN2 and association with Perrault syndrome
Year(s) Of Engagement Activity 2024
URL https://conference.manipal.edu/MGU7/