Molecular genetics of Meckel-Gruber syndrome, and functional characterization of meckelin and MKS1

Lead Research Organisation: University of Leeds
Department Name: Leeds Institute of Molecular Medicine

Abstract

Neural tube defects (NTDs) occur in 1 per 1,000 births, and cleft lip and palate occurs in 1 per 550 births. NTDs and clefting problems are the most common forms of birth defect. The most common syndromic form of NTD is Meckel-Gruber syndrome (MKS) which is an inherited condition with brain, liver and kidney defects that arise during embryonic development. In addition, cleft lip and palate is a common clinical feature of MKS. Recently, we found that MKS is caused by changes in a unique gene that makes a large, novel protein that we have called meckelin. Meckelin carries developmental signals from the outside to the inside of a cell, controlling how the cell will behave during embryonic development. This regulation is lost if meckelin is defective or absent. Meckelin is a component of primary cilia, which are finger-like projections from cells. Cilia are thought to detect and respond to chemical or mechanical cues, such as fluid flow, during the formation of the neural tube and other tubular structures. We aim to have a deeper understanding of the molecular roles of meckelin and other proteins found at cilia during embryonic development, and how these processes go wrong in human diseases. We hope that the work will also provide key insights into the causes of complex genetic diseases, including NTDs such as spina bifida, and cleft lip and palate.

Technical Summary

This proposal requests funding for one Research Associate and one post-doctoral Research Fellow to continue with my groups? autozygosity mapping work to identify new genes in an existing cohort of MKS cases, and to continue the functional characterization of MKS1 and meckelin. An existing project grant is funding yeast two-hybrid (Y2H) assays to identify proteins that interact with either meckelin or MKS1. Since the function of these proteins is unclear, we feel that Y2H assays are an essential first step to identify putative downstream effectors or components in a multisubunit complex. This proposal therefore also requests funding to allow the validation of putative interactions with meckelin and/or MKS1 that will be identified by the existing Y2H screen. To validate interactions we will use both directed ?one-to-one? Y2H assays and independent biochemical methodologies. A further aim is to identify the ligands of meckelin, which is a novel orphan receptor of unknown function. This proposal therefore seeks MRC funding for the following work:
(a) To identify new loci and disease genes for MKS, exploiting our extensive clinical resource of DNA samples from consanguineous MKS families. We will utilize the strategy of autozygosity mapping in these families, using mixed affected samples hybridised to a single Affymetrix 50K SNP chip to identify chromosomal regions that are identical-by-descent (IBD). Candidate genes in the intervals highlighted will be prioritized, in the first instance, by interrogating the primary ciliary proteome followed by direct sequencing to identify putative pathogenic mutations
(b) To confirm any meckelin and MKS1 protein-interacting partners, identified from an existing LexA-based yeast two-hybrid (Y2H) assay by, firstly, performing directed ?one-to-one? Y2H assays and, secondly, a series of biochemical assays to validate interacting protein partners and downstream effectors. These analyses will include coimmunoprecipitations and/or pulldowns of GST fusion proteins etc. that will also create a resource of reagents (antisera, vector constructs, purified GST fusion proteins etc.)
(c) identify ligands of the novel meckelin receptor with expression cloning (?panning?) using a soluble form of meckelin, comprising the extracellular N-terminal domain (residues 1 to 557) that contains a novel cysteine-rich domain (CRD). An alternative strategy will be to use the soluble form of this domain as an affinity-purification reagent for cognate ligands.
(d) target interacting partners of meckelin and/or downstream components of signalling pathways with RNAi-mediated abrogation of gene expression to determine their effect on, for example, centriole migration and ciliogenesis

Publications

10 25 50

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Adams M (2012) A meckelin-filamin A interaction mediates ciliogenesis. in Human molecular genetics

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Cantagrel V (2008) Mutations in the cilia gene ARL13B lead to the classical form of Joubert syndrome. in American journal of human genetics

 
Description diagnosis and treatment of neurodevelopmental conditions
Geographic Reach National 
Policy Influence Type Influenced training of practitioners or researchers
Impact Our research has enabled a new recognition of the broad range of phenotype for neurodevelopmental conditions such as Joubert syndrome. The identification of new genes provided more accurate prognostic testing and genetic counselling, with national NHS service testing for both Meckel-Gruber and Joubert syndromes now based at Yorkshire Regional Genetics Service. New services based on clinical whole exome sequencing has enabled testing of about 40-60 patients per annum for both the UK and for international referrals.
 
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 FP7 large co-ordinating project
Amount £850,000 (GBP)
Funding ID 241955 SYSCILIA 
Organisation European Commission 
Department Seventh Framework Programme (FP7)
Sector Public
Country European Union (EU)
Start 04/2010 
End 03/2014
 
Description KRAF project grant
Amount £98,000 (GBP)
Organisation Kids Kidney Research 
Sector Charity/Non Profit
Country United Kingdom
Start 04/2011 
End 03/2013
 
Description Newlife project grant (drug screening)
Amount £115,000 (GBP)
Organisation Newlife the Charity for Disabled Children 
Sector Charity/Non Profit
Country United Kingdom
Start 05/2013 
End 04/2015
 
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 Sir Jules Thorn Award for Biomedical Research
Amount £1,210,000 (GBP)
Funding ID 09JTA 
Organisation Sir Jules Thorn Charitable Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2010 
End 08/2016
 
Description Wellcome Trust multiuser equipment grant (Zeiss LSM880)
Amount £193,000 (GBP)
Funding ID 104918/Z/14/Z 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 09/2014 
End 08/2019
 
Title MKS patient cohort 
Description cohort of ciliopathy patients, sampled for DNA with assessment of mutation status and clinical phenotype 
Type Of Material Biological samples 
Year Produced 2007 
Provided To Others? Yes  
Impact role of RPGRIP1L in determining a retinal phenotype in ciliopathies; mutation screening in other ciliopathy genes eg ARL13B, TMEM216, TMEM138. TMEM237 etc 
 
Title Mks1 knock-out mouse 
Description Mks1 knock-out mouse model of severe ciliopathy 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Year Produced 2011 
Provided To Others? Yes  
Impact provided insights into role of dysregulated canonical Wnt signalling, cell proliferation and ciliary-related signalling into the severe ciliopathy disease phenotype, with particular emphasis on the development of the cerebullum 
 
Title Tmem67 mouse model 
Description knock-out mouse model of Meckel-Gruber syndrome; targetted mutation of the Mks3/Tmem67 gene 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Year Produced 2010 
Provided To Others? Yes  
Impact further insights into disease pathogenesis due to dysregulated Wnt signalling, cell proliferation and defects in ciliary-mediated signalling 
 
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 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 
 
Description functional characterization of ciliopathy proteins 
Organisation Eberhard Karls University of Tubingen
Department Institute for Ophthalmic Research
Country Germany 
Sector Academic/University 
PI Contribution completed a reverse genetics screen to identify novel mediators of ciliogenesis and cilia maintenance
Collaborator Contribution partners contribution protein-protein interaction data from TAP-tagging experiments, key reagents (expression constructs) and antibodies, tissue samples or sections from ciliopthy animal models
Impact Wheway G, (2013) Aberrant Wnt signalling and cellular over-proliferation in a novel mouse model of Meckel-Gruber syndrome. Dev. Biol. 377:55-66 Abdelhamed Z et al. (2013). Variable expressivity of ciliopathy neurological phenotypes that encompass Meckel-Gruber syndrome and Joubert syndrome is caused by complex de-regulated ciliogenesis, Shh and Wnt signalling defects. Hum. Mol. Genet. 22: 1358-72 Chaki M, et al. (2012). Exome capture reveals ZNF423 and CEP164 mutations, linking renal ciliopathies to DNA damage response signaling Cell 150: 533-548 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.
Start Year 2011
 
Description functional characterization of ciliopathy proteins 
Organisation Johannes Gutenberg University of Mainz
Department Department of Cell & Matrix Biology
Country Germany 
Sector Academic/University 
PI Contribution completed a reverse genetics screen to identify novel mediators of ciliogenesis and cilia maintenance
Collaborator Contribution partners contribution protein-protein interaction data from TAP-tagging experiments, key reagents (expression constructs) and antibodies, tissue samples or sections from ciliopthy animal models
Impact Wheway G, (2013) Aberrant Wnt signalling and cellular over-proliferation in a novel mouse model of Meckel-Gruber syndrome. Dev. Biol. 377:55-66 Abdelhamed Z et al. (2013). Variable expressivity of ciliopathy neurological phenotypes that encompass Meckel-Gruber syndrome and Joubert syndrome is caused by complex de-regulated ciliogenesis, Shh and Wnt signalling defects. Hum. Mol. Genet. 22: 1358-72 Chaki M, et al. (2012). Exome capture reveals ZNF423 and CEP164 mutations, linking renal ciliopathies to DNA damage response signaling Cell 150: 533-548 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.
Start Year 2011
 
Description functional characterization of ciliopathy proteins 
Organisation Radboud University Nijmegen Medical Center
Country Netherlands 
Sector Academic/University 
PI Contribution completed a reverse genetics screen to identify novel mediators of ciliogenesis and cilia maintenance
Collaborator Contribution partners contribution protein-protein interaction data from TAP-tagging experiments, key reagents (expression constructs) and antibodies, tissue samples or sections from ciliopthy animal models
Impact Wheway G, (2013) Aberrant Wnt signalling and cellular over-proliferation in a novel mouse model of Meckel-Gruber syndrome. Dev. Biol. 377:55-66 Abdelhamed Z et al. (2013). Variable expressivity of ciliopathy neurological phenotypes that encompass Meckel-Gruber syndrome and Joubert syndrome is caused by complex de-regulated ciliogenesis, Shh and Wnt signalling defects. Hum. Mol. Genet. 22: 1358-72 Chaki M, et al. (2012). Exome capture reveals ZNF423 and CEP164 mutations, linking renal ciliopathies to DNA damage response signaling Cell 150: 533-548 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.
Start Year 2011
 
Description functional characterization of ciliopathy proteins 
Organisation University of California, San Diego (UCSD)
Department Institute for Genomic Medicine
Country United States 
Sector Academic/University 
PI Contribution completed a reverse genetics screen to identify novel mediators of ciliogenesis and cilia maintenance
Collaborator Contribution partners contribution protein-protein interaction data from TAP-tagging experiments, key reagents (expression constructs) and antibodies, tissue samples or sections from ciliopthy animal models
Impact Wheway G, (2013) Aberrant Wnt signalling and cellular over-proliferation in a novel mouse model of Meckel-Gruber syndrome. Dev. Biol. 377:55-66 Abdelhamed Z et al. (2013). Variable expressivity of ciliopathy neurological phenotypes that encompass Meckel-Gruber syndrome and Joubert syndrome is caused by complex de-regulated ciliogenesis, Shh and Wnt signalling defects. Hum. Mol. Genet. 22: 1358-72 Chaki M, et al. (2012). Exome capture reveals ZNF423 and CEP164 mutations, linking renal ciliopathies to DNA damage response signaling Cell 150: 533-548 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.
Start Year 2011
 
Description medical resequencing of ciliopathy genes 
Organisation Birmingham Women's Hospital
Department Clinical Genetics
Country United Kingdom 
Sector Hospitals 
PI Contribution ascertained fmailies affected with ciliopathies, screened known genes, collated clinical data, verified mutations, exluded polymorphic variants
Collaborator Contribution access the high-throughput resequencing technology and techniques for assessing the pathogenic potential of missense variants; whole exome sequendcing of ciliopathy patients
Impact the A229T change in the RPGRIP1L gene is associated with retinal features in ciliopathies; published in Nat. Genet. 2009
Start Year 2006
 
Description medical resequencing of ciliopathy genes 
Organisation Duke University
Department Department of Cell Biology
Country United States 
Sector Academic/University 
PI Contribution ascertained fmailies affected with ciliopathies, screened known genes, collated clinical data, verified mutations, exluded polymorphic variants
Collaborator Contribution access the high-throughput resequencing technology and techniques for assessing the pathogenic potential of missense variants; whole exome sequendcing of ciliopathy patients
Impact the A229T change in the RPGRIP1L gene is associated with retinal features in ciliopathies; published in Nat. Genet. 2009
Start Year 2006
 
Description medical resequencing of ciliopathy genes 
Organisation Leeds Teaching Hospitals NHS Trust
Department Yorkshire Regional Genetics Service & Clinical Genetics
Country United Kingdom 
Sector Hospitals 
PI Contribution ascertained fmailies affected with ciliopathies, screened known genes, collated clinical data, verified mutations, exluded polymorphic variants
Collaborator Contribution access the high-throughput resequencing technology and techniques for assessing the pathogenic potential of missense variants; whole exome sequendcing of ciliopathy patients
Impact the A229T change in the RPGRIP1L gene is associated with retinal features in ciliopathies; published in Nat. Genet. 2009
Start Year 2006
 
Description medical resequencing of ciliopathy genes 
Organisation Newcastle University
Department Institute of Genetic Medicine
Country United Kingdom 
Sector Academic/University 
PI Contribution ascertained fmailies affected with ciliopathies, screened known genes, collated clinical data, verified mutations, exluded polymorphic variants
Collaborator Contribution access the high-throughput resequencing technology and techniques for assessing the pathogenic potential of missense variants; whole exome sequendcing of ciliopathy patients
Impact the A229T change in the RPGRIP1L gene is associated with retinal features in ciliopathies; published in Nat. Genet. 2009
Start Year 2006
 
Description medical resequencing of ciliopathy genes 
Organisation Sheffield Children's NHS Foundation Trust
Department Clinical Genetics
Country United Kingdom 
Sector Hospitals 
PI Contribution ascertained fmailies affected with ciliopathies, screened known genes, collated clinical data, verified mutations, exluded polymorphic variants
Collaborator Contribution access the high-throughput resequencing technology and techniques for assessing the pathogenic potential of missense variants; whole exome sequendcing of ciliopathy patients
Impact the A229T change in the RPGRIP1L gene is associated with retinal features in ciliopathies; published in Nat. Genet. 2009
Start Year 2006
 
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
 
Title NHS service testing for ciliopathies 
Description First use of clinical whole exome sequencing by the Yorkshire Regional Genetics Service for the diagnosis of ciliopathies (primary ciliary dyskinesia, Meckel-Gruber syndrome, Joubert syndrome). New services based on clinical whole exome sequencing has enabled testing of about 40-60 patients per annum for both the UK and for international referrals. 
Type Diagnostic Tool - Non-Imaging
Current Stage Of Development Wide-scale adoption
Year Development Stage Completed 2013
Development Status Under active development/distribution
Impact Improved diagnosis, prognosis and genetic counselling for ciliopathy patients and their families 
URL http://www.leedsth.nhs.uk/a-z-of-services/molecular-genetics/test-pages/meckel-and-joubert-syndromes...
 
Description Brain Awareness Day 
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 talked to sixth-form students interested in applying to do biological science/neuroscience at university at the "Brain Awareness Day" organized by the University of Leeds

requests for summer student placements, opportunity to talk to classes about medical genetics
Year(s) Of Engagement Activity 2008,2010
 
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 ISN Forefronts Symposium on PKD 
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 a general overview of my group's work on Meckel-Gruber syndrome and other ciliopathies, to an audience of researchers and clincians working on Polycystic Kidney Disease

the meeting was very useful as an informal venue to establish new collaborations with some existing collaborators
Year(s) Of Engagement Activity 2008
 
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 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 autozygosity.org website 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact a website inititated and maintained by Prof. David Bonthron at the University of Leeds to summarize our work on autozygosity mapping of recessive inherited conditions

increased clinical collaboration and publicity
Year(s) Of Engagement Activity 2008,2009,2010,2011,2012,2013,2014
URL http://www.autozygosity.org
 
Description genetics and cell biology of Meckel-Gruber syndrome 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Health professionals
Results and Impact a overview of the molecular genetics and cell biology of ciliopathies, focussing on Meckel-Gruber syndrome, to an audience of medical and clinical geneticists

useful to establish clinical collaborations on other ciliopathies (notably family ascertainment for Ivemark syndrome)
Year(s) Of Engagement Activity 2008,2009,2010,2011,2012,2013,2014
 
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