Do secondary mitochondrial DNA defects cause retinal ganglion cell death in dominant optic atrophy?
Lead Research Organisation:
Newcastle University
Department Name: Institute of Neuroscience
Abstract
Dominant optic atrophy (DOA) is one of the commonest form of inherited blindness and it results in significant visual disability. DOA is caused by irreversible damage to the optic nerve, which connects the eye to the vision centres within the brain. It is a specialised cable made up of about 2 million, highly specialised cells known as retinal ganglion cells (RGCs). In 60-70% of cases, DOA is due to a mutation in the OPA1 gene but we still do not know how this genetic defect leads to disease and why only RGCs are affected. Our preliminary findings in one large family with DOA indicate that the OPA1 mutation compromises the normal function of mitochondria. Mitochondria are essential components of all human cells and they are responsible for energy production. If insufficient energy is produced, cells cannot function properly and die. To test my hypothesis further, I will analyse blood and muscle biopsies from additional families with DOA for evidence of mitochondrial dysfunction. I will also analyse RGCs from a mouse model of DOA and determine if they contain high levels of mitochondrial DNA abnormalities. Finally, I will try to identify the gene(s) responsible for DOA in those families who not carry an OPA1 mutation. RGCs are affected in other eye conditions like glaucoma and a better understanding of their selective vulnerability will help us develop more effective treatment strategies for these blinding diseases.
Technical Summary
Dominant optic atrophy (DOA) is the most common inherited optic neuropathy and it is characterised by the progressive, focal neurodegeneration of the retinal ganglion cell (RGC) layer. DOA causes significant visual handicap, has no cure, and ~60% of cases are due to mutations in the OPA1 gene (3q28-q29). However, it is not yet established how the mutant Opa1 protein leads to disease and why RGCs are selectively targeted.
Mitochondria contain multiple copies of their own DNA (mtDNA) and both mutations (deletions and point mutations) and a reduction in the number of mtDNA molecules (depletion) can trigger a bioenergetic defect. I have recently characterised a large OPA1 family with histochemical evidence of mitochondrial dysfunction and cytochrome c oxidase negative (COX-negative) fibres in limb muscle which contained high-levels of pathogenic mtDNA deletions. Five other families with DOA have since been found to harbour multiple mtDNA deletions, only three of which had OPA1 mutations.
Our preliminary data therefore suggest that (i) the Opa1 protein is involved in mtDNA maintenance (ii) the accumulation of secondary (2 ) mtDNA defects is central to the pathophysiology of DOA and (iii) some families with DOA are likely to harbour as yet unidentified nuclear genes involved in mtDNA maintenance.
(1) Do secondary mtDNA defects lead to RGC death in DOA?
I will sequence the OPA1 gene in ten additional families with a clinical diagnosis of DOA and look for COX deficiency in limb muscle biopsies. Using laser microdissection, I will then capture single COX-negative muscle fibres and assess whether detrimental levels of 2 mtDNA defects are present (point mutations, deletions and depletion). I will also compare the range of mtDNA defects observed in these families with those seen in other disorders of mtDNA maintenance and attempt genotype-phenotype correlations. Finally, using a mouse model of DOA, I will determine whether the level of apoptosis and proportion of COX-negative cells is higher in RGCs compared to other tissues.
(2) Is DOA caused by other nuclear genes involved in mtDNA maintenance?
Through an existing collaborative network, I have access to a group of families with DOA but no OPA1 mutations. I will perform linkage analysis on these families to search for novel DOA loci and using bioinformatic techniques, I will identify and sequence candidate genes implicated in mtDNA maintenance within these regions.
Other optic neuropathies, including glaucoma, preferentially affect RGCs and understanding why these cells are selectively vulnerable will have broad implications.
Mitochondria contain multiple copies of their own DNA (mtDNA) and both mutations (deletions and point mutations) and a reduction in the number of mtDNA molecules (depletion) can trigger a bioenergetic defect. I have recently characterised a large OPA1 family with histochemical evidence of mitochondrial dysfunction and cytochrome c oxidase negative (COX-negative) fibres in limb muscle which contained high-levels of pathogenic mtDNA deletions. Five other families with DOA have since been found to harbour multiple mtDNA deletions, only three of which had OPA1 mutations.
Our preliminary data therefore suggest that (i) the Opa1 protein is involved in mtDNA maintenance (ii) the accumulation of secondary (2 ) mtDNA defects is central to the pathophysiology of DOA and (iii) some families with DOA are likely to harbour as yet unidentified nuclear genes involved in mtDNA maintenance.
(1) Do secondary mtDNA defects lead to RGC death in DOA?
I will sequence the OPA1 gene in ten additional families with a clinical diagnosis of DOA and look for COX deficiency in limb muscle biopsies. Using laser microdissection, I will then capture single COX-negative muscle fibres and assess whether detrimental levels of 2 mtDNA defects are present (point mutations, deletions and depletion). I will also compare the range of mtDNA defects observed in these families with those seen in other disorders of mtDNA maintenance and attempt genotype-phenotype correlations. Finally, using a mouse model of DOA, I will determine whether the level of apoptosis and proportion of COX-negative cells is higher in RGCs compared to other tissues.
(2) Is DOA caused by other nuclear genes involved in mtDNA maintenance?
Through an existing collaborative network, I have access to a group of families with DOA but no OPA1 mutations. I will perform linkage analysis on these families to search for novel DOA loci and using bioinformatic techniques, I will identify and sequence candidate genes implicated in mtDNA maintenance within these regions.
Other optic neuropathies, including glaucoma, preferentially affect RGCs and understanding why these cells are selectively vulnerable will have broad implications.
Organisations
- Newcastle University, United Kingdom (Lead Research Organisation)
- Cardiff University, United Kingdom (Collaboration)
- National Institute of Health and Medical Research (INSERM) (Collaboration)
- University of Bologna, Italy (Collaboration)
- Angers University Hospital (CHU Angers) (Collaboration)
- Eberhard Karls University Tuebingen, Germany (Collaboration)
- University of Cambridge, United Kingdom (Fellow)
People |
ORCID iD |
Patrick Yu Wai Man (Principal Investigator / Fellow) |
Publications

Alavi MV
(2009)
Subtle neurological and metabolic abnormalities in an Opa1 mouse model of autosomal dominant optic atrophy.
in Experimental neurology

Angebault C
(2015)
Recessive Mutations in RTN4IP1 Cause Isolated and Syndromic Optic Neuropathies.
in American journal of human genetics

Astuti D
(2017)
Monogenic diabetes syndromes: Locus-specific databases for Alström, Wolfram, and Thiamine-responsive megaloblastic anemia.
in Human mutation

Bailie M
(2013)
Visual and psychological morbidity among patients with autosomal dominant optic atrophy
in Acta Ophthalmologica

Bannwarth S
(2015)
Reply: CHCHD10 mutations in Italian patients with sporadic amyotrophic lateral sclerosis.
in Brain : a journal of neurology

Bannwarth S
(2015)
Reply: Is CHCHD10 Pro34Ser pathogenic for frontotemporal dementia and amyotrophic lateral sclerosis?
in Brain : a journal of neurology

Bannwarth S
(2016)
Reply: High prevalence of CHCHD10 mutations in patients with frontotemporal dementia from China.
in Brain : a journal of neurology

Bannwarth S
(2014)
Reply: Mutations in the CHCHD10 gene are a common cause of familial amyotrophic lateral sclerosis.
in Brain : a journal of neurology

Bannwarth S
(2014)
A mitochondrial origin for frontotemporal dementia and amyotrophic lateral sclerosis through CHCHD10 involvement.
in Brain : a journal of neurology
Description | Investigating disease mechanisms and therapeutic strategies in inherited optic neuropathies |
Amount | £85,000 (GBP) |
Organisation | University of Cambridge |
Department | Isaac Newton Trust |
Sector | Academic/University |
Country | United Kingdom |
Start | 07/2019 |
End | 06/2021 |
Description | MRC Centenary Early Career Award |
Amount | £15,000 (GBP) |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 10/2012 |
End | 09/2013 |
Description | Moorfields Special Trustees Research Award |
Amount | £130,000 (GBP) |
Organisation | Moorfields Eye Charity |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 10/2016 |
End | 09/2019 |
Description | NIHR Rare Diseases Translational Research Collaboration |
Amount | £310,000 (GBP) |
Organisation | National Institute for Health Research |
Department | NIHR Biomedical Research Centre |
Sector | Public |
Country | United Kingdom |
Start | 09/2016 |
End | 08/2018 |
Description | NIHR Rare Diseases Translational Research Collaboration |
Amount | £250,000 (GBP) |
Organisation | National Institute for Health Research |
Sector | Public |
Country | United Kingdom |
Start | 08/2014 |
End | 08/2016 |
Description | What disease mechanisms contribute to multisystem tissue involvement in dominant optic atrophy due to OPA1 mutations? |
Amount | £1,126,871 (GBP) |
Funding ID | G1002570 |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 03/2012 |
End | 08/2016 |
Title | Inherited Eye Diseases Database |
Description | An extensive up-to-date database of patients with inherited eye diseases, with a primary focus on mitochondrial genetic disorders. |
Type Of Material | Database/Collection of Data/Biological Samples |
Provided To Others? | No |
Impact | DOA and LHON are the two most commmon inherited optic nerve disorders in the general population. This database has allowed us to define the epidemiology of autosomal dominant optic atrophy (DOA) in the North of England and has contributed to the successful completion of a Phase II randomised controlled trial for Leber Hereditary Optic Neuropathy (LHON). |
Title | OPA1 Tissue Biobank |
Description | Setting up of fibroblasts and myoblast cell lines carrying pathogenic OPA1 mutations. |
Type Of Material | Cell line |
Provided To Others? | No |
Impact | This valuable tissue biobank will be used for future projects looking at OPA1 disease mechanisms. |
Description | Angers OPA1 Collaboration |
Organisation | Angers University Hospital (CHU Angers) |
Department | Department of Biochemistry and Genetics |
Country | France |
Sector | Academic/University |
PI Contribution | Exchange of patient data and tissue samples |
Collaborator Contribution | Exchange of patient data and tissue samples |
Impact | PMID:20974897 PMID:20157015 |
Start Year | 2007 |
Description | Bologna OPA1 Collaboration |
Organisation | University of Bologna |
Department | Department of Neurologial Sciences |
Country | Italy |
Sector | Academic/University |
PI Contribution | We are working closely with Dr Carelli's team in Bologa to understand the development of multisystem disease in patients harbouring OPA1 mutations. |
Collaborator Contribution | Dr Carelli's team have provided us with clinical data for a meta-analysis of the phenotypes seen in patients with OPA1 mutations. |
Impact | PMID: 20974897 PMID: 20157015 |
Start Year | 2007 |
Description | Cardiff OPA1 Mouse Collaboration |
Organisation | Cardiff University |
Department | School of Optometry and Vision Sciences |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | I have analysed these OPA1 mouse tissues as part of my ongoing PhD research project. |
Collaborator Contribution | Our collaborators in Cardiff have provided us with tissues from an OPA1 mouse model of dominant optic atrophy. |
Impact | PMID: 19443720 PMID: 20157015 |
Start Year | 2008 |
Description | Montpellier OPA1 Collaboration |
Organisation | National Institute of Health and Medical Research (INSERM) |
Department | Institute of Neuroscience Montpellier |
Country | France |
Sector | Academic/University |
PI Contribution | We are working with Dr Guy Lenaers team in Montpellier to investigate the role of OPA1 in mitochondrial DNA replication. |
Collaborator Contribution | Dr Leaners' team have provided tissue samples and experimental data for our research in Newcastle. |
Impact | PMID: 20974897 PMID: 20157015 |
Start Year | 2008 |
Description | Tuebingen OPA1 Mouse Collaboration |
Organisation | Eberhard Karls University of Tübingen |
Department | Institute for Ophthalmic Research |
Country | Germany |
Sector | Academic/University |
PI Contribution | I have analysed these OPA1 mouse tissues as part of my ongoing PhD research project. |
Collaborator Contribution | Our collaborators in Tuebingen have provided us with tissues from a second OPA1 mouse model of dominant optic atrophy - different from the Cardiff one. |
Impact | PMID: 19815013 PMID: 19181907 |
Start Year | 2008 |
Description | ARVO - Florida 2008 |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Other academic audiences (collaborators, peers etc.) |
Results and Impact | Oral presentation at ARVO, which is the largest annual scientific meeting devoted to basic research into eye disorders. New collaborations |
Year(s) Of Engagement Activity | 2008 |
Description | EUROMIT 7 - Stockholm 2008 |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Other academic audiences (collaborators, peers etc.) |
Results and Impact | Posters presented at EUROMIT 7 which is the largest meeting devoted to research into mitochondrial disorders. New collaborations |
Year(s) Of Engagement Activity | 2008 |
Description | Fighting Blindness - Dublin 2009 |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | Yes |
Geographic Reach | International |
Primary Audience | Participants in your research and patient groups |
Results and Impact | Meeting on translational eye research. The participants came from various backgrounds: clinicians, scientists, and patient groups - both local and international. New collaborations - especially with international patient associations involved in the fight against blindness. |
Year(s) Of Engagement Activity | 2009 |