Examining the coupling of small GTPase activation and metabolism of the phosphoinositide lipid PI(3,5)P2 in Charcot Marie Tooth Type 4 Neuropathies
Lead Research Organisation:
University of Liverpool
Department Name: Institute of Translational Medicine
Abstract
Charcot-Marie Tooth type 4 (CMT4) neuropathies are a group of diseases characterized by a failure of myelin, the "insulation" for the nerves sending signals to muscles in the body. Patients who have CMT4 generally develop it early in life, meaning that they face a lifetime of needing assistance with mobility and basic tasks. It is a progressive disorder, where the myelin insulation slowly stops wrapping properly around the nerves it is meant to insulate. This stops the nerve from sending signals properly to the limbs, leading to both sensory and motor impairment (particularly in the more distant limbs). As this disease slowly gets worse over time, there is a possibility that if we understand what is going wrong, the disease process could be arrested or even reversed by the appropriate therapy.
We wish to study several related genes which all cause CMT4. These have different functions, but work together to move proteins to and from the surface of the cell (we call this trafficking). CMT4 pathologies occur because of the failure of proper trafficking in the cells that make myelin, meaning proteins that should be at the surface of the myelin-making cells don't arrive properly or at the wrong time.
CMT4 pathologies are caused by mutation any of 11 different genes. 5 of these genes (the ones we want to study) make enzymes. 3 of these enzymes (called Frabin, MTMR13, and MTMR5) switch on GTPases. 4 enzymes (called MTMR2, MTMR13, MTMR5 and Fig4) act on a rare lipid (PI(3,5)P2) which helps conduct trafficking in the cell by adding a 'tag' which tells you where inside the cell you are during the trafficking process. Small GTPases are another kind of 'tag'- when they are switched on, they instruct certain groups of proteins to collect on the membrane. Together, lipids like PI(3,5)P2 and proteins like small GTPases can specify a time and a place for the process of moving proteins to the cell surface. For CMT4 patients we still don't know where the important pool of PI(3,5)P2 lipid is in the cell, and what actions that should be co-ordinated by small GTPases are failing to happen in CMT4 patients with mutations in these genes.
The enzymes mentioned above are the most promising targets for therapies, as they are potentially druggable, or can have their enzymatic activities replaced by other means. This project aims to understand what is going wrong in the cells making myelin and identify the best targets for therapy, preliminary to studies for therapeutic strategies.
We wish to study several related genes which all cause CMT4. These have different functions, but work together to move proteins to and from the surface of the cell (we call this trafficking). CMT4 pathologies occur because of the failure of proper trafficking in the cells that make myelin, meaning proteins that should be at the surface of the myelin-making cells don't arrive properly or at the wrong time.
CMT4 pathologies are caused by mutation any of 11 different genes. 5 of these genes (the ones we want to study) make enzymes. 3 of these enzymes (called Frabin, MTMR13, and MTMR5) switch on GTPases. 4 enzymes (called MTMR2, MTMR13, MTMR5 and Fig4) act on a rare lipid (PI(3,5)P2) which helps conduct trafficking in the cell by adding a 'tag' which tells you where inside the cell you are during the trafficking process. Small GTPases are another kind of 'tag'- when they are switched on, they instruct certain groups of proteins to collect on the membrane. Together, lipids like PI(3,5)P2 and proteins like small GTPases can specify a time and a place for the process of moving proteins to the cell surface. For CMT4 patients we still don't know where the important pool of PI(3,5)P2 lipid is in the cell, and what actions that should be co-ordinated by small GTPases are failing to happen in CMT4 patients with mutations in these genes.
The enzymes mentioned above are the most promising targets for therapies, as they are potentially druggable, or can have their enzymatic activities replaced by other means. This project aims to understand what is going wrong in the cells making myelin and identify the best targets for therapy, preliminary to studies for therapeutic strategies.
Technical Summary
This project aims to understand the function of a group of related enzymes in membrane trafficking, and how their loss may cause Charcot Marie Tooth Type 4 neuropathies. We aim to identify critical points in the exo-endocytic cycle which may be open to therapeutic manipulation to arrest or reverse this progressive disorder. We will use proteins produced in human cell suspension cultures as material to identify small GTPase interactors of CMT4 genes using label-free differential mass spectrometry and then characterize these interactions in model cells, human patient fibroblasts (where available) and in in vitro Schwann cell- neuron co-cultures. We will use lentiviral treatments of Schwann cells to establish cell-autonomous effects of CMT4 gene manipulations in myelinating cells in these co-cultures. Our second aim will establish tools to acutely manipulate the lipid PI(3,5)P2 in cell culture and in vitro myelinating culture models using the CRY2-CIBN optogenetic system, so as to establish the location and function of the pool of this lipid in (dis)myelination.
Planned Impact
Apart from the Academic beneficiaries outlined above, our research will have long-term relevance for several groups:
Directly (2-5 years)- patients and families suffering from Charcot Marie Tooth Type 4 Neuropathies (CMT4). CMT4 is an early-onset disease, where patients often need considerable care and adjustments made to their living situation over the course of a long life. The economic and social benefits of even small improvements in mobility in these patients are considerable. This project aims to find where therapeutic interventions could be made, and to build in vitro assays that could subsequently be used for screens for therapies. Moreover, we will produce results that will help interested parties understand how CMT4 develops, and to help patients and families engage with the process of discovering therapies.
This project will also be training researchers in a novel and growing field of cell biology, and in the use of cutting-edge techniques for transient manipulation of cell biology. The PDRA employed by this project will have an unique and valuable set of experimental tools with which to develop their further career.
In the case of other human pathologies- our data has relevance for neurodegenerative disorders (ALS and PLS) through our studies and manipulation of Fig4 activity with the attendant financial and social benefit if these studies can point the way to therapeutic interventions in these disorders.
In the longer term (5-15 years): It is becoming rapidly apparent that the rare lipid PI(3,5)P2 is at the nexus of several critical signalling pathways (please see academic beneficiaries for a fuller description of the processes so far found to be regulated by PI(3,5)P2). Some of these pathways, such as cell-survival and aging signalling regulated by mTOR, or insulin signaling are pathways that if we can understand and manipulate, will have great implications for public health, given our aging and increasingly sedentary population. Our work here will produce new tools to manipulate this lipid and to understand functionally what is happening to cells where PI(3,5)P2 in specific cellular compartments, and will contribute to ongoing efforts to manipulate cell signaling for improving health and quality of life in the general population.
Economically- this study is aimed towards establishing phenotypes which can be subsequently used for drug discovery screens. This has a direct commercial relevance for biotechnology in the UK, not least because we are studying processes which may be relevant to significantly more than the one set of diseases we are focused on (as I have outlined above). The generation of further basic knowledge and intellectual property centred around this membrane trafficking pathway has the potential to be an unexplored and commercially significant area in biomedical/pharmaceutical healthcare.
Directly (2-5 years)- patients and families suffering from Charcot Marie Tooth Type 4 Neuropathies (CMT4). CMT4 is an early-onset disease, where patients often need considerable care and adjustments made to their living situation over the course of a long life. The economic and social benefits of even small improvements in mobility in these patients are considerable. This project aims to find where therapeutic interventions could be made, and to build in vitro assays that could subsequently be used for screens for therapies. Moreover, we will produce results that will help interested parties understand how CMT4 develops, and to help patients and families engage with the process of discovering therapies.
This project will also be training researchers in a novel and growing field of cell biology, and in the use of cutting-edge techniques for transient manipulation of cell biology. The PDRA employed by this project will have an unique and valuable set of experimental tools with which to develop their further career.
In the case of other human pathologies- our data has relevance for neurodegenerative disorders (ALS and PLS) through our studies and manipulation of Fig4 activity with the attendant financial and social benefit if these studies can point the way to therapeutic interventions in these disorders.
In the longer term (5-15 years): It is becoming rapidly apparent that the rare lipid PI(3,5)P2 is at the nexus of several critical signalling pathways (please see academic beneficiaries for a fuller description of the processes so far found to be regulated by PI(3,5)P2). Some of these pathways, such as cell-survival and aging signalling regulated by mTOR, or insulin signaling are pathways that if we can understand and manipulate, will have great implications for public health, given our aging and increasingly sedentary population. Our work here will produce new tools to manipulate this lipid and to understand functionally what is happening to cells where PI(3,5)P2 in specific cellular compartments, and will contribute to ongoing efforts to manipulate cell signaling for improving health and quality of life in the general population.
Economically- this study is aimed towards establishing phenotypes which can be subsequently used for drug discovery screens. This has a direct commercial relevance for biotechnology in the UK, not least because we are studying processes which may be relevant to significantly more than the one set of diseases we are focused on (as I have outlined above). The generation of further basic knowledge and intellectual property centred around this membrane trafficking pathway has the potential to be an unexplored and commercially significant area in biomedical/pharmaceutical healthcare.
Organisations
People |
ORCID iD |
| Laura Swan (Principal Investigator) |
Publications
100,000 Genomes Project Pilot Investigators
(2021)
100,000 Genomes Pilot on Rare-Disease Diagnosis in Health Care - Preliminary Report.
in The New England journal of medicine
Abicht A
(2018)
Mitochondrial and nuclear disease panel (Mito-aND-Panel): Combined sequencing of mitochondrial and nuclear DNA by a cost-effective and sensitive NGS-based method.
in Molecular genetics & genomic medicine
Atalaia A
(2021)
Correction to: A guide to writing systematic reviews of rare disease treatments to generate FAIRcompliant datasets: building a Treatabolome.
in Orphanet journal of rare diseases
Balaraju S
(2020)
Congenital myasthenic syndrome with mild intellectual disability caused by a recurrent SLC25A1 variant.
in European journal of human genetics : EJHG
Bansagi B
(2018)
Multifocal demyelinating motor neuropathy and hamartoma syndrome associated with a de novo PTEN mutation.
in Neurology
Bardhan M
(2021)
Correction: Megaconial congenital muscular dystrophy secondary to novel CHKB mutations resemble atypical Rett syndrome.
in Journal of human genetics
Bardhan M
(2021)
Megaconial congenital muscular dystrophy secondary to novel CHKB mutations resemble atypical Rett syndrome.
in Journal of human genetics
Boczonadi V
(2018)
Mitochondrial oxodicarboxylate carrier deficiency is associated with mitochondrial DNA depletion and spinal muscular atrophy-like disease
in Genetics in Medicine
Boczonadi V
(2018)
Mutations in glycyl-tRNA synthetase impair mitochondrial metabolism in neurons.
in Human molecular genetics
Boczonadi V
(2018)
The role of tRNA synthetases in neurological and neuromuscular disorders.
in FEBS letters
Burns DT
(2018)
Variants in EXOSC9 Disrupt the RNA Exosome and Result in Cerebellar Atrophy with Spinal Motor Neuronopathy.
in American journal of human genetics
Cipriani S
(2018)
Neuromuscular Junction Changes in a Mouse Model of Charcot-Marie-Tooth Disease Type 4C.
in International journal of molecular sciences
Cortese A
(2020)
Cerebellar ataxia, neuropathy, vestibular areflexia syndrome due to RFC1 repeat expansion.
in Brain : a journal of neurology
Cotta A
(2021)
Muscle fat replacement and modified ragged red fibers in two patients with reversible infantile respiratory chain deficiency.
in Neuromuscular disorders : NMD
De Boer E
(2021)
A MT-TL1 variant identified by whole exome sequencing in an individual with intellectual disability, epilepsy, and spastic tetraparesis.
in European journal of human genetics : EJHG
De Boer E
(2021)
Correction: A MT-TL1 variant identified by whole exome sequencing in an individual with intellectual disability, epilepsy, and spastic tetraparesis.
in European journal of human genetics : EJHG
Diebold I
(2019)
HADHA and HADHB gene associated phenotypes - Identification of rare variants in a patient cohort by Next Generation Sequencing.
in Molecular and cellular probes
Donkervoort S
(2020)
Biallelic loss of function variants in SYT2 cause a treatable congenital onset presynaptic myasthenic syndrome.
in American journal of medical genetics. Part A
Edgar JR
(2020)
A dysfunctional endolysosomal pathway common to two sub-types of demyelinating Charcot-Marie-Tooth disease.
in Acta neuropathologica communications
Estephan EP
(2018)
Clinical variability of early-onset congenital myasthenic syndrome due to biallelic RAPSN mutations in Brazil.
in Neuromuscular disorders : NMD
Gangfuß A
(2022)
A de novo CSDE1 variant causing neurodevelopmental delay, intellectual disability, neurologic and psychiatric symptoms in a child of consanguineous parents.
in American journal of medical genetics. Part A
Gangfuß A
(2021)
NEW GENES AND DISEASES
in Neuromuscular Disorders
Gungor S
(2021)
Autosomal recessive variants in TUBGCP2 alter the ?-tubulin ring complex leading to neurodevelopmental disease.
in iScience
Hathazi D
(2020)
Metabolic shift underlies recovery in reversible infantile respiratory chain deficiency
in The EMBO Journal
Hathazi D
(2021)
INPP5K and SIL1 associated pathologies with overlapping clinical phenotypes converge through dysregulation of PHGDH.
in Brain : a journal of neurology
Hiz Kurul S
(2022)
High diagnostic rate of trio exome sequencing in consanguineous families with neurogenetic diseases.
in Brain : a journal of neurology
Jennings MJ
(2021)
Targeted Therapies for Hereditary Peripheral Neuropathies: Systematic Review and Steps Towards a 'treatabolome'.
in Journal of neuromuscular diseases
Jennings MJ
(2021)
Intracellular Lipid Accumulation and Mitochondrial Dysfunction Accompanies Endoplasmic Reticulum Stress Caused by Loss of the Co-chaperone DNAJC3.
in Frontiers in cell and developmental biology
Juneja M
(2018)
PFN2 and GAMT as common molecular determinants of axonal Charcot-Marie-Tooth disease.
in Journal of neurology, neurosurgery, and psychiatry
Kagiava A
(2021)
AAV9-mediated Schwann cell-targeted gene therapy rescues a model of demyelinating neuropathy.
in Gene therapy
Keogh MJ
(2017)
PLP1 mutations and central demyelination: Evidence from electrophysiologic phenotyping in female manifesting carriers.
in Neurology. Clinical practice
Klopstock T
(2019)
Safety and efficacy of deferiprone for pantothenate kinase-associated neurodegeneration: a randomised, double-blind, controlled trial and an open-label extension study.
in The Lancet. Neurology
Knuutinen O
(2020)
Homozygous TAF1C variants are associated with a novel childhood-onset neurological phenotype
in Clinical Genetics
Kohlschmidt N
(2021)
Molecular pathophysiology of human MICU1 deficiency.
in Neuropathology and applied neurobiology
Kullar PJ
(2018)
Heterozygous SSBP1 start loss mutation co-segregates with hearing loss and the m.1555A>G mtDNA variant in a large multigenerational family.
in Brain : a journal of neurology
Larrea D
(2019)
MFN2 mutations in Charcot-Marie-Tooth disease alter mitochondria-associated ER membrane function but do not impair bioenergetics.
in Human molecular genetics
Laššuthová P
(2018)
Novel SBF2 mutations and clinical spectrum of Charcot-Marie-Tooth neuropathy type 4B2.
in Clinical genetics
Lochmüller H
(2021)
Results from a 3-year Non-interventional, Observational Disease Monitoring Program in Adults with GNE Myopathy.
in Journal of neuromuscular diseases
Lorenzoni PJ
(2018)
How to Spot Congenital Myasthenic Syndromes Resembling the Lambert-Eaton Myasthenic Syndrome? A Brief Review of Clinical, Electrophysiological, and Genetics Features.
in Neuromolecular medicine
Luscher A
(2019)
Lowe syndrome-linked endocytic adaptors direct membrane cycling kinetics with OCRL in Dictyostelium discoideum.
in Molecular biology of the cell
Manole A
(2020)
De Novo and Bi-allelic Pathogenic Variants in NARS1 Cause Neurodevelopmental Delay Due to Toxic Gain-of-Function and Partial Loss-of-Function Effects.
in American journal of human genetics
Matalonga L
(2020)
Improved Diagnosis of Rare Disease Patients through Systematic Detection of Runs of Homozygosity.
in The Journal of molecular diagnostics : JMD
McMacken G
(2020)
Behr syndrome and hypertrophic cardiomyopathy in a family with a novel UCHL1 deletion.
in Journal of neurology
McMacken GM
(2019)
Salbutamol modifies the neuromuscular junction in a mouse model of ColQ myasthenic syndrome.
in Human molecular genetics
McWilliam SJ
(2021)
The complex interplay between kidney injury and inflammation.
in Clinical kidney journal
Mingirulli N
(2020)
Clinical presentation and proteomic signature of patients with TANGO2 mutations.
in Journal of inherited metabolic disease
Minnerop M
(2018)
Reply: POLR3A variants in hereditary spastic paraplegia and ataxia.
in Brain : a journal of neurology
Munro B
(2019)
Nucleoside supplementation modulates mitochondrial DNA copy number in the dguok -/- zebrafish.
in Human molecular genetics
| Description | as Chair of the mitochondrial group within the ERN-NMD I participate in endorsing and making guidelines for mitochondrial diseases |
| Geographic Reach | Europe |
| Policy Influence Type | Influenced training of practitioners or researchers |
| Impact | As the Chair of the mitochondrial group within the EURO-NMD reference network I participate in making diagnosis and management of patients with mitochondrial diseases harmonised in Europe |
| URL | https://ern-euro-nmd.eu/ |
| Description | Horizon 2020 |
| Amount | € 15,000,000 (EUR) |
| Organisation | European Union |
| Sector | Public |
| Country | European Union (EU) |
| Start | 01/2018 |
| End | 12/2023 |
| Description | Protein processing and secretion in a new cause of CMD, INPP5K mutation. |
| Amount | £224,962 (GBP) |
| Funding ID | 18GRO-PG36-0270 |
| Organisation | Muscular Dystrophy UK |
| Sector | Charity/Non Profit |
| Country | United Kingdom |
| Start | 01/2019 |
| End | 01/2022 |
| Description | Research Grant |
| Amount | £15,000 (GBP) |
| Funding ID | RG170076 |
| Organisation | The Royal Society |
| Sector | Charity/Non Profit |
| Country | United Kingdom |
| Start | 11/2017 |
| End | 11/2018 |
| Title | BN-PAGE |
| Description | functional analysis of human patient cell lines |
| Type Of Material | Cell line |
| Provided To Others? | No |
| Impact | we revealed the pathomechanism of mitochondrial disease in 20 patients |
| Title | Identified molecular serum biomarkers in CMT |
| Description | We identify proteins in sera of patients and mouse models with Charcot-Marie-Tooth disease (CMT) with characteristics that make them suitable as biomarkers in clinical practice and therapeutic trials. |
| Type Of Material | Physiological assessment or outcome measure |
| Year Produced | 2022 |
| Provided To Others? | Yes |
| Impact | Molecular markers scalable for clinical use are critical for the development of effective treatments and the design of clinical trials. We collected serum from mouse models of CMT1A (C61 het), CMT2D (GarsC201R, GarsP278KY), CMT1X (Gjb1-null), CMT2L (Hspb8K141N) and from CMT patients with genotypes including CMT1A (PMP22d), CMT2D (GARS), CMT2N (AARS) and other rare genetic forms of CMT. The severity of neuropathy in the patients was assessed by the CMT Neuropathy Examination Score (CMTES). We performed multitargeted proteomics on both sample sets to identify proteins elevated across multiple mouse models and CMT patients. We detected that GDF15 and NCAM1 are useful biomarkers in CMT and tehy should be further investigated in clinical trials. |
| URL | https://pubmed.ncbi.nlm.nih.gov/35148379/ |
| Title | TRMU cells |
| Description | we have obtained cells (fibrobalsts and myoblasts) from a patient and established a special technique to study 2-thiolation of mt-tRNAs |
| Type Of Material | Cell line |
| Provided To Others? | No |
| Impact | We are currently investigating the possible role of 2-thiolation as a possible disease mechanism in reversible COX deficiency as part of the project |
| Title | genetically encoded sensor of lysosomal pH |
| Description | we built a ratiometric reporter of lysosomal pH coupled to a purification tag which allows correlated live measurements of lysosomal physiology with mass spectroscopic analysis of lysosomal protein recruitment. The sensor is simpler to use than similar approaches using dyes/endocytic probes and stable for days of continuous imaging in culture. |
| Type Of Material | Biological samples |
| Year Produced | 2020 |
| Provided To Others? | Yes |
| Impact | the probe is one of the highly-requested probes on Addgene, is simpler to use than other approaches, and offers more information (in the form of proteomic analysis of lysosomes with a known physiological state) than other techniques. |
| URL | https://www.addgene.org/browse/article/28211549/ |
| Title | iPSC neuronal conversion |
| Description | We established the conversion of neurons from iPSCs of patients with mitochondrial disease. |
| Type Of Material | Cell line |
| Year Produced | 2020 |
| Provided To Others? | No |
| Impact | We are currently working on these cells and we will publish our results. |
| Title | induced neuronal progenitor cells |
| Description | We can successfully convert human finroblasts into induced neuronal progenitor cells. |
| Type Of Material | Model of mechanisms or symptoms - human |
| Provided To Others? | No |
| Impact | We have already converted 4 patient and 2 contol cell lines into induced neuronal progenitor cells. Currently the analysis of mitochondrial function is in progress in these cells. |
| Title | studying the neuromuscular junction |
| Description | co-investigator on a multi-user equipment funded by Wellcome to study electrophysiology of the neuromuscular junction |
| Type Of Material | Physiological assessment or outcome measure |
| Year Produced | 2018 |
| Provided To Others? | Yes |
| Impact | no impact yet, equipment is currently being set up |
| Title | zebrafish |
| Description | I used zebrafish to model human disease. |
| Type Of Material | Model of mechanisms or symptoms - mammalian in vivo |
| Provided To Others? | No |
| Impact | Published a paper (Boczonadi et al. 2014) |
| Title | Treatabolome |
| Description | My group has participated in the "Treatabolome" project, which is part of the EU Solve-RD. We have performed a systematic review and established the database for treatable genes and variants in Charcot-Marie-Tooth Disease (CMT). |
| Type Of Material | Computer model/algorithm |
| Year Produced | 2020 |
| Provided To Others? | Yes |
| Impact | We collated evidence for the effectiveness of pharmacological and gene-based treatments for hereditary peripheral neuropathies. We searched several databases for randomised controlled trials (RCT), observational studies and case reports of therapies in hereditary peripheral neuropathies. Two investigators extracted and analysed the data independently, assessing study quality using the Oxford Centre for Evidence Based Medicine 2011 Levels of Evidence in conjunction with the Jadad scale. The 'treatable' variants highlighted in this project will be flagged in the treatabolome database to alert clinicians at the time of the diagnosis and enable timely treatment of patients with hereditary peripheral neuropathies. |
| URL | https://pubmed.ncbi.nlm.nih.gov/32773395/ |
| Title | bioinformatic analysis of RNAseq |
| Description | performed RNAseq in several human cell and muscle samples and analysed different parameters to gain understanding of the metabolic signature of neurogenetic diseases |
| Type Of Material | Data analysis technique |
| Year Produced | 2017 |
| Provided To Others? | No |
| Impact | papers are currently in progress |
| Title | proteomic analysis of cells/tissues |
| Description | performed proteomic analysis of paatient cells and skeletal muscle samples |
| Type Of Material | Data analysis technique |
| Year Produced | 2017 |
| Provided To Others? | Yes |
| Impact | papers in progress |
| Description | Consequitur - cohort of patients from Turkey for WES |
| Organisation | Dokuz Eylül University |
| Country | Turkey |
| Sector | Academic/University |
| PI Contribution | We collaborate with Dr. Yavuz Oktay and Dr. Semra Hiz on identiying new disease genes in consanguineous Turkish families with various neurogenetic diseases. |
| Collaborator Contribution | Collected 400 families and DNA samples, perfomred phenotyping |
| Impact | We are currently writing abstracts for conferences from the first results and drafting papers. |
| Start Year | 2016 |
| Description | Identifying novel disease genes in hereditary motor neuropathies |
| Organisation | University of Miami |
| Country | United States |
| Sector | Academic/University |
| PI Contribution | We have identified mutations in a novel disease gene in a family with autosomal dominant hereditary motor neuropathy. |
| Collaborator Contribution | The collaborators also had one family with another mutation in the same gene. |
| Impact | We have published a paper together in AJHG. |
| Start Year | 2014 |
| Description | Metablic testing of serum and lymphoblastoid cells of patients with motor neuropathy |
| Organisation | University of Antwerp |
| Country | Belgium |
| Sector | Academic/University |
| PI Contribution | We collected serum and blood samples of patients with hereditary motor neuropathies and Prof. Vincent Timmermann`s group converted them to lymphoblastoid cells and conduct metabolomics studies |
| Collaborator Contribution | Prof. Timmermann`s group convert the blood cells to lymphoblastoid cells. |
| Impact | samples are currently being analysed |
| Start Year | 2016 |
| Description | Metabolic measurements in mitochondrial carrier protein deficiency |
| Organisation | University of Cambridge |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | We have patient samples for metabolic measurements to Dr. Christian Frezza`s laboratory. |
| Collaborator Contribution | We will receive the results soon and will have a joint publication. |
| Impact | no output yet |
| Start Year | 2013 |
| Description | collecting new variants of INPP5K mutations in patients |
| Organisation | University of Southampton |
| Department | Clinical and Experimental Sciences |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | enzymology, creation of cell lines and cell biological analysis of new INPP5K patient variants |
| Collaborator Contribution | partners are clinicians. |
| Impact | Identification of a novel disease mechanism caused by INPP5K mutation (ongoing) |
| Start Year | 2019 |
| Description | confirming the role of PTPMT1 in human disease |
| Organisation | University College London |
| Department | Institute of Neurology |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | We made a zebrafish model of this novel gene and supported that it causes decreased cardiolipin and movement problems. |
| Collaborator Contribution | The UCL team (Rob Pitceathly) identified another patient and did cardiolipin studies. |
| Impact | paper is currently being drafted |
| Start Year | 2020 |
| Description | search for biomarkers in CMT |
| Organisation | University of Antwerp |
| Country | Belgium |
| Sector | Academic/University |
| PI Contribution | We have performed targeted proteomics on serum of patients with CMT. We extended the analysis on mouse models of CMT. |
| Collaborator Contribution | We have received serum from mouse models of CMT from Prof. Vincent Timmermann`s team. We search for biomarkers in CMT in this collaboration. |
| Impact | submitted an abstract to the UK MRC Translational Research Conference (22-23 April, UCL) |
| Start Year | 2019 |
| Title | A Study of Bezafibrate in Mitochondrial Myopathy" (NUTH NHS Trust, 2015) |
| Description | We are testing the feasibility of bezafibrate supplementation in MELAS. Trial has been finished. We published the paper very recently in EMBO Mol Med |
| Type | Therapeutic Intervention - Drug |
| Current Stage Of Development | Early clinical assessment |
| Year Development Stage Completed | 2019 |
| Development Status | Under active development/distribution |
| Impact | trial has not shown clinical benefit |
| Description | creating video about patient journey for European Joint Program |
| Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Media (as a channel to the public) |
| Results and Impact | We actively participated in making a video about a patient journey of a Turkish patient who we dignosed within our research for the European Joint Program activities. |
| Year(s) Of Engagement Activity | 2019 |
| URL | https://twitter.com/GA4GH/status/1186993739991900165?s=17 |