Functional genomics identification and characterization of novel disease genes, mechanisms and pathways of ciliogenesis

Lead Research Organisation: University of Leeds
Department Name: School of Medicine

Abstract

Cilia are small structures which protrude from the surface of most animal cells like antennae. Like antennae, they receive signals from other cells and their surroundings, and help the cell behave appropriately. This is especially important in development, and defects in cilia lead to a range of human developmental diseases called "ciliopathies". These conditions range from severe, lethal conditions that involve complex defects in multiple organs including the brain, to retinitis pigmentosa (RP) which is a form of hereditary, progressive sight loss. Scientists still do not fully understand how cilia help to control brain and retina development. Although these conditions are individually rare, collectively they are a common cause of morbidity and mortality in babies and young children but remain difficult to diagnose and treat.

This research proposes to identify genes that are either defective ("mutated") in ciliopathies, or otherwise contribute to the formation of a cilium either individually or as part of a pathway. To achieve this aim, we will take advantage of recent exciting advances in genetic technology that allow us to evaluate the contribution of every human gene to cilia formation ("reverse genetics screen"). We are uniquely placed to do this work and the team of investigators have a proven track record of success in this field: we have formed excellent research partnerships with families, their clinicians and other workers in the field to participate in gene identification studies; we have the appropriate state-of-the-art technology, image analysis tools and experience; and we have already produced and validated the very large data-set from the screen that we now wish to exploit more extensively in the present research proposal. We will study key genes ("screen hits") and their contributions to cilia formation, and, in particular we will use special cell systems that more closely model brain and retinal tissue. To do this, we will use both mouse and human stem cells differentiated into neuronal precursors, neurons and retinal cells. Importantly, this approach allows us to study cilia in retinal tissue derived from patients with RP.

The identification of new genes in cilia formation provides two major benefits. Firstly, accurate genetic testing then becomes possible for patients and families, with improvements in diagnosis and genetic counselling. Secondly, important and often unexpected scientific insights are made into disease mechanisms and into the normal function of the disease gene that can lead to new treatments. In particular, we have preliminary evidence from the screen that certain forms of RP, for which the disease mechanism has been unclear previously, may be caused by defective cilia formation in the retina. A better understanding of these processes may provide opportunities for developing drugs or new treatments to prevent disease progression in common forms of retinal degeneration. We also expect new insights into the causes of other common conditions such as polycystic kidney disease, spina bifida and congenital heart defects.

Technical Summary

This proposal builds upon our recent results from the first whole-genome reverse genetics screen to identify genes involved in ciliogenesis. This has used high-throughput siRNA-based visual screening, with secondary and validation screens identifying 68 candidate genes. Our proposal integrates existing and new functional genomics data-sets with variant data from existing gene discovery programmes, secondary screens to validate hits, and protein-protein interaction data to confirm that potential ciliary proteins bind to retinitis pigmentosum (RP)-associated spliceosome components. We will then use tertiary screens that include functional annotation with cell biology in physiologically-relevant cell models or zebrafish mutagenesis models. Specific aims are to understand the novel roles of G-protein-coupled receptors (GPCRs) and pre-mRNA processing factors (PRPFs) in ciliogenesis, and how loss of these can lead to neurodevelopmental defects or retinal degeneration, by using stem cell-derived model systems. We will study the role of hit GPCRs in ciliogenesis during neural progenitor differentiation of mouse embryonic stem (ESCs) into neuroepithelial cells and/or radial glial cells. To study the potential ciliary roles of hit PRPFs in a physiologically-relevant tissue, we will use differentiated retinal pigmentary epithelium and photoreceptor-induced cultures derived from induced pluripotent stem cells (iPSCs). Importantly, this approach allows us to study cilia in retinal tissue derived from patients with RP. We aim to demonstrate the clinical utility and validity of an integrated "systems medicine" approach and its ability to make relevant predications about disease causality. The research will complete the functional annotation of genes contributing to ciliogenesis, developing our understanding of the basic biology of primary cilia. It may also identify novel therapeutic strategies to slow disease progression for ciliopathies or RP.

Planned Impact

Recent advances have improved the molecular diagnosis of children with a known or suspected ciliopathy, and reduced the burden and disruption of a "diagnostic odyssey" for families. For clinicians, the identification of a new gene can also reduce misdiagnosis or late diagnosis, inform the establishment of proper care pathways for ciliopathy patients, and prioritize those patients that can most benefit from future targeted therapies. Although ciliopathies are a heterogenous group of rare inherited conditions, collectively they are a common cause of perinatal morbidity and mortality (1 in 500 births) and remain difficult to diagnose and treat. For example, in the UK, about 4000 patients require renal replacement therapy (dialysis and transplantation) as a result of cystic kidney disease that leads to kidney failure. There are currently no preventative treatments or new therapeutic interventions for cystic kidney disease that may modify disease progression or the long-term outlook of patients.

The identification of new genes and disease pathways provides insights into normal human physiology and development, and the underlying mechanism of common conditions such as obesity, hypertension, cystic kidney disease and congenital heart disease thus benefiting the wider population. In families with a ciliopathy, the identification of a novel disease gene immediately permits the offer of genetic testing to at-risk relatives. Carrier tests and prenatal diagnosis can also encourage informed reproductive choices for families. Recently, we have established NHS service testing for ciliopathies (including Meckel-Gruber syndrome, Joubert syndrome and primary ciliary dyskinesia) using next-generation clonal sequencing at Yorkshire Regional Clinical Genetics Service. However, this work is often limited by the extreme genetic heterogeneity of the ciliopathies, and the inability to interpret "private" mutations in single families as pathogenic or variants of unknown significance.

To solve this problem we have used a functional genomics strategy to evaluate the contribution of every human gene to ciliogenesis. Our data-set has already identified new disease genes, mechanisms and pathways including unexpected roles for pre-mRNA processing factors (PRPFs). PRPF mutations are the second most common cause of autosomal dominant retinitis pigmentosum (RP) affecting up to 1 in 3500 people. We are very confident that our functional genomics screen has high specificity for ciliary processes and that our multidisciplinary approach allows the functional annotation of many new genes. We will integrate functional genomics with WES variant data from existing gene discovery programmes, followed by cell biology in physiologically-relevant cell or zebrafish mutant models. We aim to demonstrate the clinical utility and validity of integrated "systems medicine" annotation and its ability to make relevant predications about disease causality. We are also keen to retain key researchers with key skills in functional genomics so that their expertise can stimulate the adoption of the broader "systems medicine" approach. The development of a strong interface between gene discovery, functional annotation and diagnostic development work is therefore an indirect but important added benefit of this research.

The identification of new disease genes and pathways may enable the future rational design of therapeutics to modify or treat cystic kidney disease, retinal degeneration or ciliopathy disease progression, or improve the long-term outlook of patients with these conditions. Since these conditions result from absence of normal protein, they can in principle be corrected by gene-replacement, therapeutic approaches now undergoing Phase II clinical trials. Patients in whom mutations are found can therefore be given a clearer prognosis and prioritised for these new treatments, making inherited disease a top priority for further characterization.

Publications

10 25 50
 
Description recessive conditions
Geographic Reach Local/Municipal/Regional 
Policy Influence Type Influenced training of practitioners or researchers
Impact greater investment in clinical genetics and training of genetic counsellors, greater awareness of recessive conditions and rare diseases
 
Description Bilateral BBSRC-SFI (structure-function relationships in the ciliary transition zone)
Amount £576,400 (GBP)
Funding ID BB/P007791/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 04/2017 
End 03/2021
 
Description Elucidating splicing factor function and retinal splicing programmes: developing new therapeutic strategies for splicing factor retinitis pigmentosa
Amount £1,456,000 (GBP)
Funding ID MR/T017503/1 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 01/2020 
End 12/2024
 
Description PhD Training Fellowship for Clinicians "Developing variant interpretation pipelines for inherited retinal diseases and ciliopathies: using medical genomics to improve diagnostic yield"
Amount £250,000 (GBP)
Funding ID UNS81212 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2018 
End 09/2021
 
Description Pre-clinical testing of new therapeutic treatments for cystic kidney disease
Amount £200,000 (GBP)
Funding ID GN2628 
Organisation University of Leeds 
Sector Academic/University
Country United Kingdom
Start 07/2018 
End 06/2021
 
Description multi-user equipment grant
Amount £429,000 (GBP)
Funding ID 208395/Z/17/Z 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 09/2017 
End 08/2022
 
Description project grant
Amount £200,000 (GBP)
Funding ID GN2628 
Organisation Action Medical Research 
Sector Charity/Non Profit
Country United Kingdom
Start 03/2018 
End 02/2021
 
Title effectors of ciliogenesis 
Description list of validated candidate genes implicated in ciliogenesis, cilia maintenance and cilia length growth as a result of a whole genome cell-based reverse genetics visual screen primary list: ca. 600 genes secondary screen list: 174 genes tertiary validated genes: ca. 42 genes selected functional candidates: 14 genes other date includes RNA-Seq expression data from non-ciliated vs. ciliated cell-lines 
Type Of Material Technology assay or reagent 
Year Produced 2013 
Provided To Others? Yes  
Impact methodlogy of assessing cell numbers in the screen described in this publication: Elmehdawi F, et al. (2013) Human Homologue of Drosophila Ariadne (HHARI) is a marker of cellular proliferation associated with nuclear bodies. Exp. Cell Res. 319:161-172. Wheway G, et al. (2015). An siRNA-based functional genomics screen for the identification of regulators of ciliogenesis and ciliopathy genes. Nat. Cell. Biol. 17: 1074-87 
URL http://www.syscilia.org
 
Title genome-edited cell-lines 
Description a panel of isogenic knock-out cell-lines for key ciliary genes (validated by sequencing, western blotting and assays of ciliary function) to be used in reverse genetics screening, drug screening and as model systems of ciliopathies. New crispant cell-lines include null alleles in CEP290 and base-edited specific class 5 (pathogenic) and class 3 (unknown significance) variants. 
Type Of Material Cell line 
Year Produced 2017 
Provided To Others? Yes  
Impact The CEP290 knock-out cell-line is being used as a model system for renal cystic disease in preclinical studies that have arisen from drug screens of clinical development compounds 
 
Title ciliated cell-line gene expression 
Description RNA sequencing data for two cell-lines in profilerating (non-ciliated) and quiescent (ciliated) cell cycle stages; all performed for n=3 biological replicates 
Type Of Material Database/Collection of data 
Year Produced 2015 
Provided To Others? Yes  
Impact data is archived in SRA study PRJNA298886 'ciliated_cell_lines', accession SRP064956; data accession numbers: SRX1353143, SRX1411364, SRX1411444, SRX1411451, SRX1411453 and SRX1411455 publication: Slaats GG, Wheway G, Foletto V, Szymanska K, van Balkom BWM, Logister I, Den Ouden K, Keijzer-Veen MG, Lilien MR, Knoers NV, Johnson CA, Giles RH (2015). Screen-based identification and validation of four novel ion channels as regulators of renal ciliogenesis. J. Cell Sci. 128: 4550-9 
URL http://www.ncbi.nlm.nih.gov/sra
 
Title effectors of ciliogenesis 
Description list of validated candidate genes implicated in ciliogenesis, cilia maintenance and cilia length growth as a result of a whole genome cell-based reverse genetics visual screen primary list: ca. 600 genes secondary screen list: 174 genes tertiary validated genes: ca. 42 genes selected functional candidates: 14 genes other date includes RNA-Seq expression data from non-ciliated vs. ciliated cell-lines 
Type Of Material Database/Collection of data 
Provided To Others? No  
Impact Wheway G*, Schmidts M*, Mans DA*, Szymanska K*, Nguyen T-MT*, ...69 others... Doherty D+, Mitchison HM+, Roepman R+, Johnson CA+ (2015). An siRNA-based functional genomics screen for the identification of regulators of ciliogenesis and ciliopathy genes. Nat. Cell. Biol. 17: 1074-87 
 
Title gene expression in retinal tissues 
Description A large RNA-sequencing data-set for retinitis pigmentosa patients mutated in the pre-mRNA-splicing factor PRPF31, using patient-derived tissues that comprise: fibroblasts, iPSCs, retinal pigment epithelium and differentiated 3D optic cup organoids (predominantly photoreceptors) The data-set has been analyzed for expression level, differential expression and differential exon usage by current analysis software (DESeq2, DEXSeq, rMATS) 
Type Of Material Database/Collection of data 
Provided To Others? No  
Impact The data-set supports an on-going research study with the aim of submitting a manuscript and follow-on grant funding in mid-2017 
 
Description molecular cell biology of ciliopathies 
Organisation University of Oxford
Department Sir William Dunn School of Pathology
Country United Kingdom 
Sector Academic/University 
PI Contribution assessed ciliogenesis in a cell model systems (knockdown and patient cells); confocal microscopy
Collaborator Contribution expertise in confocal and electron microscopy, bioinformatics techniques and data mining, access to monoclonals
Impact insight into the role of ciliary proteins on formation of the primary cilium (eg dockng of the basal body organelle); publication in J. Cell Sci. with on-going collaboration; generated pilot data for a whole-genome siRNA reverse genetics screen
 
Description molecular organization of the ciliary transition zone 
Organisation University College Dublin
Department UCD Conway Institute of Biomedical annd Biomolecular Research
Country Ireland 
Sector Academic/University 
PI Contribution The primary cilium is a complex sensory organelle of vertebrate cells, and these collaborations focus on a key compartment known as the ciliary transition zone. We will address the intricate molecular organisation of sub-structures and functional modules within cilia, and how these provide the structural basis for compartmentalization and selective permeability during ciliary signalling and protein trafficking. The overall aim of this research is to investigate the function and localization of proteins within the ciliary apparatus using super-resolution microscopy and soft X-ray tomography, with the possibility of correlative cryoSIM and cellular electron microscopy. The establishment of correlative light-electron microscopy will provide the opportunity for further detailed insights into the function and molecular organization of ciliary components, allowing the delineation of new spatial relationships and molecular organization within the native, functioning organelle. My research team provides key reagents (antibodies, non-antibody binding proteins, genome-edited cell-lines, clinical patient material) and expertise in the cell biology of cilia.
Collaborator Contribution The collaborators provide access and expertise for functional testing in an in vivo model system (C. elegans), CRISPR-Cas9 genome editing of knock-ins (eg the split GFP system), STED super resolution microscopy, preparation and high-pressure vitrification of cryosamples for cryoEM or SXT, access to the B24 beamline at the Diamond light source, construction and interpretation of tomograms etc.
Impact One active grant from the BBSRC-SFI partnership "Bilateral BBSRC-SFI: Structure-function relationships in the ciliary transition zone" ref. BB/P007791/1 (start 1 Apr 2017)
Start Year 2016
 
Description molecular organization of the ciliary transition zone 
Organisation University of Leeds
Department Astbury Centre for Structural Molecular Biology
Country United Kingdom 
Sector Academic/University 
PI Contribution The primary cilium is a complex sensory organelle of vertebrate cells, and these collaborations focus on a key compartment known as the ciliary transition zone. We will address the intricate molecular organisation of sub-structures and functional modules within cilia, and how these provide the structural basis for compartmentalization and selective permeability during ciliary signalling and protein trafficking. The overall aim of this research is to investigate the function and localization of proteins within the ciliary apparatus using super-resolution microscopy and soft X-ray tomography, with the possibility of correlative cryoSIM and cellular electron microscopy. The establishment of correlative light-electron microscopy will provide the opportunity for further detailed insights into the function and molecular organization of ciliary components, allowing the delineation of new spatial relationships and molecular organization within the native, functioning organelle. My research team provides key reagents (antibodies, non-antibody binding proteins, genome-edited cell-lines, clinical patient material) and expertise in the cell biology of cilia.
Collaborator Contribution The collaborators provide access and expertise for functional testing in an in vivo model system (C. elegans), CRISPR-Cas9 genome editing of knock-ins (eg the split GFP system), STED super resolution microscopy, preparation and high-pressure vitrification of cryosamples for cryoEM or SXT, access to the B24 beamline at the Diamond light source, construction and interpretation of tomograms etc.
Impact One active grant from the BBSRC-SFI partnership "Bilateral BBSRC-SFI: Structure-function relationships in the ciliary transition zone" ref. BB/P007791/1 (start 1 Apr 2017)
Start Year 2016
 
Description stem cell-derived models of retinitis pigmentosa and retinal diseases 
Organisation Leeds Teaching Hospitals NHS Trust
Country United Kingdom 
Sector Public 
PI Contribution Recruited patients with splicing factor-related forms of retinitis pigmentosa; sampled, cultured and characterized dermal fibroblasts by RNA sequencing to determine expression profiles and splicing patterns; characterization of fibroblasts, induced pluripotent stem cells, retinal pigmentary epithelial cells and neural retinal-like cultures by high content imaging; established differentiation of retinal cell lineages (retinal pigment epithelium and retinal organoids) from induced pluripotent stem cell (iPSC) lines; full charaterization of cell function and marker expression; generation of crispant knock-in and base-editing of patient mutations as cellular models of retinal disease
Collaborator Contribution Derivation of induced pluripotent stem cells, retinal pigmentary epithelial cells and neural retinal-like cultures from undiseased control and patient dermal fibroblasts, as well as induced pluripotent stem cell (iPSC) lines; full charaterization of cell function and marker expression;
Impact applications for further funding to MRC; establishment of a stem cell facility at Leeds Institute of Medical Research
Start Year 2015
 
Description stem cell-derived models of retinitis pigmentosa and retinal diseases 
Organisation Newcastle University
Department International Centre for Life
Country United Kingdom 
Sector Academic/University 
PI Contribution Recruited patients with splicing factor-related forms of retinitis pigmentosa; sampled, cultured and characterized dermal fibroblasts by RNA sequencing to determine expression profiles and splicing patterns; characterization of fibroblasts, induced pluripotent stem cells, retinal pigmentary epithelial cells and neural retinal-like cultures by high content imaging; established differentiation of retinal cell lineages (retinal pigment epithelium and retinal organoids) from induced pluripotent stem cell (iPSC) lines; full charaterization of cell function and marker expression; generation of crispant knock-in and base-editing of patient mutations as cellular models of retinal disease
Collaborator Contribution Derivation of induced pluripotent stem cells, retinal pigmentary epithelial cells and neural retinal-like cultures from undiseased control and patient dermal fibroblasts, as well as induced pluripotent stem cell (iPSC) lines; full charaterization of cell function and marker expression;
Impact applications for further funding to MRC; establishment of a stem cell facility at Leeds Institute of Medical Research
Start Year 2015
 
Description stem cell-derived models of retinitis pigmentosa and retinal diseases 
Organisation University of Leeds
Department Astbury Centre for Structural Molecular Biology
Country United Kingdom 
Sector Academic/University 
PI Contribution Recruited patients with splicing factor-related forms of retinitis pigmentosa; sampled, cultured and characterized dermal fibroblasts by RNA sequencing to determine expression profiles and splicing patterns; characterization of fibroblasts, induced pluripotent stem cells, retinal pigmentary epithelial cells and neural retinal-like cultures by high content imaging; established differentiation of retinal cell lineages (retinal pigment epithelium and retinal organoids) from induced pluripotent stem cell (iPSC) lines; full charaterization of cell function and marker expression; generation of crispant knock-in and base-editing of patient mutations as cellular models of retinal disease
Collaborator Contribution Derivation of induced pluripotent stem cells, retinal pigmentary epithelial cells and neural retinal-like cultures from undiseased control and patient dermal fibroblasts, as well as induced pluripotent stem cell (iPSC) lines; full charaterization of cell function and marker expression;
Impact applications for further funding to MRC; establishment of a stem cell facility at Leeds Institute of Medical Research
Start Year 2015
 
Description structural biology of ciliary proteins 
Organisation University of Leeds
Department Astbury Centre for Structural Molecular Biology
Country United Kingdom 
Sector Academic/University 
PI Contribution protein purification of ciliary protein domains, production and charaterization of "Affimer " artifical binding proteins and their use as novel detection reagents in super resolution microscopy; optimizartion of cellular soft X-ray tomography of primary cilia 9using teh SXt B24 beamline at Diamond)
Collaborator Contribution protein production for Affimer generation and crysallography trials; optimization of novel analysis methods for super resolution microscopy (two colour dSTORM, STED); live cell imaging
Impact collation of preliminary data into a larger UKRI grant application
Start Year 2018
 
Description super-resolution microscopy of ciliary proteins 
Organisation University College Dublin
Department UCD Conway Institute of Biomedical annd Biomolecular Research
Country Ireland 
Sector Academic/University 
PI Contribution We have developed a panel of antibodies specific for ciliary proteins that have been used for both PALM and STORM imaging. We are developing non-antibody binding proteins (Adhirons) for this application.
Collaborator Contribution Provided the facilities and technical expertise for both STORM and PALM image capture, processing and analysis.
Impact The collaboration has led to the publication: Lambacher NJ, et al. (2015). TMEM107 recruits ciliopathy proteins to anchored periodic subdomains of the ciliary transition zone membrane and is mutated in Joubert syndrome. Nat. Cell Biol. doi: 10.1038/ncb3273 New funding application have been made to the MRC and BBSRC/SFI joint funding stream
Start Year 2015
 
Description super-resolution microscopy of ciliary proteins 
Organisation University of Leeds
Department Faculty of Biological Sciences
Country United Kingdom 
Sector Academic/University 
PI Contribution We have developed a panel of antibodies specific for ciliary proteins that have been used for both PALM and STORM imaging. We are developing non-antibody binding proteins (Adhirons) for this application.
Collaborator Contribution Provided the facilities and technical expertise for both STORM and PALM image capture, processing and analysis.
Impact The collaboration has led to the publication: Lambacher NJ, et al. (2015). TMEM107 recruits ciliopathy proteins to anchored periodic subdomains of the ciliary transition zone membrane and is mutated in Joubert syndrome. Nat. Cell Biol. doi: 10.1038/ncb3273 New funding application have been made to the MRC and BBSRC/SFI joint funding stream
Start Year 2015
 
Title Pre-clinical testing of ROCK2 inhibition as a new therapeutic treatments for cystic kidney disease 
Description Cilia are small structures that protrude from the surface of most animal cells like antennae. Like antennae, they receive signals from other cells and their surroundings to ensure that cells form tissues correctly. This is important in development, and defects in cilia cause inherited developmental disorders called "ciliopathies". These invariably have cystic kidney disease as a feature, and are a major cause of childhood morbidity and mortality, with about 5000 patients in the UK needing either dialysis or transplantation every year as a result of kidney failure. The lack of preventative or therapeutic treatments has created the opportunity to "repurpose" existing approved drugs as potential treatments. We have identified and validated one approved drug that improves cilia formation and function, determined the drug's target protein (ROCK2) and molecular mechanism of action, and have tested efficacy in animal models of ciliopathies. We now want to test the lead drug and related derivatives in cell-based disease models of ciliopathies and kidney cysts. We will use kidney organoids that we can artificially produce from special "induced pluripotent stem cells" (iPSCs) that can be differentiated into embryonic organ systems. This is the continuation of an existing project into a more extensive validation programme ("pre-clinical testing"). The overall aim is to re-purpose and translate a known drug into Phase II clinical trials in less than 5 years. 
Type Therapeutic Intervention - Drug
Current Stage Of Development Initial development
Year Development Stage Completed 2019
Development Status Actively seeking support
Impact Initial studies have leveraged further internal funding for development work, and we are activity seeking external funding for pre-clinical studies in disease models. Funding bodies include LifeArc, Action Medical Research, and Harrington UK Rare Disease scholarship. 
 
Description BioJapan2017 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Industry/Business
Results and Impact presented current methodologies used for functional interpretation of mutations in rare Mendelian conditions using CRISPR-Cas9 genome and base editing; the presentation was to a large mixed audience of industry, big pharma and basic reseachers followed by a debate on ethic issues
Year(s) Of Engagement Activity 2017
 
Description Cafe Scientifique 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Patients, carers and/or patient groups
Results and Impact About 50 attendees to the Cafe Scientifique meeting in Feb 2020; I presented on recent advances in the diagnosis and treatment of inherited blindness, and was able to answer questions and speak to patients and supporters after the formal presentation.
Year(s) Of Engagement Activity 2020
 
Description FASEB "Polycystic Kidney Disease" meeting 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact to facillitate and establish research collabirations, with critique of current research
Year(s) Of Engagement Activity 2017
 
Description Johnson Lab Twitter feed 
Form Of Engagement Activity Engagement focused website, blog or social media channel
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Twitter feed for the lab group which reports on our professional activities and events
Year(s) Of Engagement Activity 2020
URL https://twitter.com/johnsoncilialab
 
Description Joubert syndrome scientific meeting 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation keynote/invited speaker
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact imporant discussion on the improved methods for diagnosis of Joubert syndrome and other ciliopathies, as well as new insights into pathogenic mechanisms

promoting new collaborations with workers in the field of Joubert syndrome
Year(s) Of Engagement Activity 2013
 
Description Midbrain/Hindbrain Malformations and Hydrocephalus workshop 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Type Of Presentation keynote/invited speaker
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact important opportunity to compare methods of diagnosis for ciliopathies and provided new insights into development of the cerebullum and posterior fossa structures

initiated new collaborations as part of on-going discussions
Year(s) Of Engagement Activity 2014
 
Description PEGS Boston 2018 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Industry/Business
Results and Impact presented current methodologies used for functional interpretation of mutations in rare Mendelian conditions using CRISPR-Cas9 genome and base editing; the presentation was to a large mixed audience of industry, big pharma and basic reseachers followed by a debate on ethic issues
Year(s) Of Engagement Activity 2018
 
Description UK Cilia Club 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact informal research club for reseachers in the north of England and Scotland; first meeting was in Sheffield Sept 2014, with on-going meetings planned for every 6 months in Leeds, Newcastle adn Edinburgh

new collaboration with University of Newcastle
Year(s) Of Engagement Activity 2014,2015,2016,2017,2018
 
Description school out-reach activities 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact discussed careers in medical research with about 60 Year 12 and 13 students on a visit and presentation at their school; 10 had a follow-on visit to the lab to discuss research methods
Year(s) Of Engagement Activity 2015,2016,2017,2018