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.
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.
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
Zhang T
(2022)
Stable W Isotope Measurements of Geological Reference Materials and Tungsten Ore Minerals by Double Spike MC-ICP-MS
in Geostandards and Geoanalytical Research
Vogel G
(2023)
Genotypic and phenotypic spectrum of infantile liver failure due to pathogenic TRMU variants
in Genetics in Medicine
Vila-Sanjurjo A
(2023)
Structural analysis of mitochondrial rRNA gene variants identified in patients with deafness.
in Frontiers in physiology
Smith TB
(2023)
Novel homozygous variants in PRORP expand the genotypic spectrum of combined oxidative phosphorylation deficiency 54.
in European journal of human genetics : EJHG
Nguyen-Dien GT
(2023)
FBXL4 suppresses mitophagy by restricting the accumulation of NIX and BNIP3 mitophagy receptors.
in The EMBO journal
Ng KY
(2022)
Nonstop mRNAs generate a ground state of mitochondrial gene expression noise.
in Science advances
Mavraki E
(2022)
Genetic testing for mitochondrial disease: the United Kingdom best practice guidelines
in European Journal of Human Genetics
Kaiyrzhanov R
(2022)
Phenotypic continuum of NFU1 -related disorders
in Annals of Clinical and Translational Neurology
Erdinc D
(2023)
Pathological variants in TOP3A cause distinct disorders of mitochondrial and nuclear genome stability.
in EMBO molecular medicine
Elwan M
(2022)
Changing faces of mitochondrial disease: autosomal recessive POLG disease mimicking myasthenia gravis and progressive supranuclear palsy
in BMJ Neurology Open
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 |