Genetic models of human disease
Lead Research Organisation:
University of Edinburgh
Abstract
Notwithstanding that the 20-25,000 genes that humans have is fewer than was previously thought, the function is known for only a fraction of them. Whilst some experiments can be done on cells in culture, or on yeast or bacteria, a full understanding of the function of many genes can only come from studying them in the whole organism. Humans with genetic disease provide one way of studying the effect of the lack of a particular gene. As all mammals have virtually the same genetic content as humans, another approach is to study mice with genetic mutations.
We have identified mouse models of a number of human diseases, including genetic eye defects such as glaucoma, congenital diaphragm problems, neurological disease, kidney disease and stroke. Understanding how defective genes lead to disease not only helps understand those diseases that have a genetic component but also leads to the biological pathways that are affected in non-genetic disease, and may ultimately aid in the design of therapies for many.
We have identified mouse models of a number of human diseases, including genetic eye defects such as glaucoma, congenital diaphragm problems, neurological disease, kidney disease and stroke. Understanding how defective genes lead to disease not only helps understand those diseases that have a genetic component but also leads to the biological pathways that are affected in non-genetic disease, and may ultimately aid in the design of therapies for many.
Technical Summary
The aim of this programme is to use mouse genetics and genomics to explore gene function, as it relates to human development, physiology and disease and to identify mouse models of human disease. We have previously discovered more than 25 new mutations that affect eye development and function, and, with the aid of the mouse genome sequence, have identified the affected gene in almost all of them. Most of the mutations result in lethality when homozygous and identify genes that are important in a range of biological processes. In addition, we have used deletions to reveal recessive mutations that localise to particular genomic locations.
We will continue characterisation of several of these mutant genes, two of which have known human disease homologues; Pax2, causing eye and kidney defects and Lmx1b causing nail-patella syndrome, and including glaucoma. This latter gene is subject to a collaboration with Simon John in the Jackson Labs, USA. A third mutant, for which we are still to confirm the affected gene, results in the congenital diagphragmatic hernia, a common human birth defect.
One of the mutations revealed in the deletion analysis results in hair loss, and is a mutation in a palmityl transferase protein, which results in loss of a palmitoylation activity. Palmitoylation is a dynamic process which regulates the association of a protein with the cell membrane. The key substrate of this enzyme is unknown, although we have some affected candidates. This is the subject of a collaborative project with Ian Smyth at Monash.
We have carried out a screen for novel recessive embryonic mutations, and identified a number of interesting genes which interact with the hedgehog signalling pathway.
We have extended our collaboration with MRC Mammalian Genetics Unit, Harwell to screen for recessive mutations that affect vision and eye development. We have at least 5 new confirmed recessive mutations affecting eye morphogenesis, and have identified the affected gene in three of them.
We are partners in the Eumodic programme, in which several hundred "knockout" mouse lines will be generated and comprehensively screened for defects in many systems of clinical importance. We will take any lines which demonstrate vision or other eye problems and extend the analysis to a more detailed histological level.
We will continue characterisation of several of these mutant genes, two of which have known human disease homologues; Pax2, causing eye and kidney defects and Lmx1b causing nail-patella syndrome, and including glaucoma. This latter gene is subject to a collaboration with Simon John in the Jackson Labs, USA. A third mutant, for which we are still to confirm the affected gene, results in the congenital diagphragmatic hernia, a common human birth defect.
One of the mutations revealed in the deletion analysis results in hair loss, and is a mutation in a palmityl transferase protein, which results in loss of a palmitoylation activity. Palmitoylation is a dynamic process which regulates the association of a protein with the cell membrane. The key substrate of this enzyme is unknown, although we have some affected candidates. This is the subject of a collaborative project with Ian Smyth at Monash.
We have carried out a screen for novel recessive embryonic mutations, and identified a number of interesting genes which interact with the hedgehog signalling pathway.
We have extended our collaboration with MRC Mammalian Genetics Unit, Harwell to screen for recessive mutations that affect vision and eye development. We have at least 5 new confirmed recessive mutations affecting eye morphogenesis, and have identified the affected gene in three of them.
We are partners in the Eumodic programme, in which several hundred "knockout" mouse lines will be generated and comprehensively screened for defects in many systems of clinical importance. We will take any lines which demonstrate vision or other eye problems and extend the analysis to a more detailed histological level.
Organisations
- University of Edinburgh, United Kingdom (Collaboration, Lead Research Organisation)
- University of Leeds, United Kingdom (Collaboration)
- University College London, United Kingdom (Collaboration)
- MRC Harwell, United Kingdom (Collaboration)
- Cardiff University, United Kingdom (Collaboration)
- Scotland's Rural College (Collaboration)
- The Wellcome Trust Sanger Institute (Collaboration)
- The Jackson Laboratory (Collaboration)
- Medical Research Council (Collaboration)
- University of Bath, United Kingdom (Collaboration)
People |
ORCID iD |
Ian Jackson (Principal Investigator) |
Publications

Banks G
(2015)
Genetic background influences age-related decline in visual and nonvisual retinal responses, circadian rhythms, and sleep
in Neurobiology of Aging

Carpanini SM
(2014)
A novel mouse model of Warburg Micro syndrome reveals roles for RAB18 in eye development and organisation of the neuronal cytoskeleton.
in Disease models & mechanisms

Chen J
(2014)
Spinster homolog 2 (spns2) deficiency causes early onset progressive hearing loss.
in PLoS genetics

Cross SH
(2019)
Missense Mutations in the Human Nanophthalmos Gene TMEM98 Cause Retinal Defects in the Mouse.
in Investigative ophthalmology & visual science

Cross SH
(2011)
The Opdc missense mutation of Pax2 has a milder than loss-of-function phenotype.
in Human molecular genetics

Cross SH
(2014)
A dominant-negative mutation of mouse Lmx1b causes glaucoma and is semi-lethal via LDB1-mediated dimerization [corrected].
in PLoS genetics

Cross SH
(2020)
The nanophthalmos protein TMEM98 inhibits MYRF self-cleavage and is required for eye size specification.
in PLoS genetics

Diggle CP
(2014)
HEATR2 plays a conserved role in assembly of the ciliary motile apparatus.
in PLoS genetics

Findlay AS
(2020)
Fam151b, the mouse homologue of C.elegans menorin gene, is essential for retinal function.
in Scientific reports

Findlay AS
(2018)
Mouse Idh3a mutations cause retinal degeneration and reduced mitochondrial function.
in Disease models & mechanisms
Description | Imperial College committee |
Geographic Reach | National |
Policy Influence Type | Participation in advisory committee |
Impact | Universities are improving animal care conditions |
Description | Infrafrontier advisory |
Geographic Reach | Europe |
Policy Influence Type | Participation in a advisory committee |
Description | NC3Rs Board |
Geographic Reach | National |
Policy Influence Type | Participation in a advisory committee |
Impact | National Centre for 3Rs influences academia, government and industry in their use of animals in research |
Description | NC3Rs optimal strategy |
Geographic Reach | National |
Policy Influence Type | Contribution to new or Improved professional practice |
Impact | More effective use of mice on biomedical research, better welfare outcomes |
URL | https://www.nc3rs.org.uk/3rs-resources/breeding-and-colony-management/colony-management-best-practic... |
Description | Caledonian Research Foundation Fellowship |
Amount | £110,000 (GBP) |
Organisation | University of Edinburgh |
Department | Caledonian Research Foundation |
Sector | Academic/University |
Country | United Kingdom |
Start |
Description | MRC Project grant |
Amount | £1,084,794 (GBP) |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 08/2013 |
End | 09/2016 |
Description | Responsive Mode |
Amount | £408,069 (GBP) |
Funding ID | BB/P017479/1 |
Organisation | Biotechnology and Biological Sciences Research Council (BBSRC) |
Sector | Public |
Country | United Kingdom |
Start | 09/2017 |
End | 09/2020 |
Title | Arl13-FUCCI |
Description | Transgenic mouse line that reports cell cycle stage by fluorescence, whilst simultaneously fluorescently labelling,cila |
Type Of Material | Model of mechanisms or symptoms - mammalian in vivo |
Year Produced | 2018 |
Provided To Others? | Yes |
Impact | Distribution to several labs, Publication PMID: 30458140 |
Title | Fam151b, the mouse homologue of C.elegans menorin gene, is essential for retinal function |
Description | mice mutant in Fam151 genes indicating role of Fam151b in retinal function |
Type Of Material | Model of mechanisms or symptoms - mammalian in vivo |
Year Produced | 2020 |
Provided To Others? | Yes |
Impact | publication in scientific journal |
Title | Missense Mutations in the Human Nanophthalmos Gene TMEM98 Cause Retinal Defects in the Mouse |
Description | 2 mouse models of human missense mutations in Tmem98 associated with nanophthalmos |
Type Of Material | Model of mechanisms or symptoms - mammalian in vivo |
Year Produced | 2019 |
Provided To Others? | Yes |
Impact | publication in scientific journal |
Title | Mouse Idh3a mutations cause retinal degeneration and reduced mitochondrial function |
Description | mouse model for retinal degeneration due to IDH3 deficiency |
Type Of Material | Model of mechanisms or symptoms - mammalian in vivo |
Year Produced | 2018 |
Provided To Others? | Yes |
Impact | publication in scientific journal |
Description | Aligianis |
Organisation | Medical Research Council (MRC) |
Department | MRC Human Genetics Unit |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | supervision of joint student |
Collaborator Contribution | joint student, clinical background on patients |
Impact | publication PMID:24764192 |
Start Year | 2010 |
Description | Andrew Jackson |
Organisation | Medical Research Council (MRC) |
Department | MRC Human Genetics Unit |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | analysed mouse mutant embryos |
Collaborator Contribution | led project |
Impact | paper PMID: 22579044 |
Start Year | 2011 |
Description | Gillingwater/Cousin |
Organisation | University of Edinburgh |
Department | Centre for Integrative Physiology |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | PhD student analysing mouse mutant |
Collaborator Contribution | training and advice on neuroscience methods |
Impact | publication PMID:24764192 |
Start Year | 2010 |
Description | Harwell |
Organisation | MRC Harwell |
Department | MRC Mammalian Genetics Unit |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | We take the mice, map and identify the genes affected and analyse the phenotype |
Collaborator Contribution | screening of mice for chemically induced mutant eye phenotypesidentification of mutant mouse strains, and generation of mutant mouse models |
Impact | PMID: 20943750 PMID: 20056676 PMID: 18765564 PMID: 16825286 PMID: 24809698 PMID: 23902802 PMID: 23633653 PMID: 23902802 PMID: 24809698 PMID: 25179226 PMID: 25736793 PMID: 26542706 PMID: 27534441 PMID: 30478029 other papers pre 2006 other papers in preparation |
Description | Harwell |
Organisation | MRC Harwell |
Department | MRC Mammalian Genetics Unit |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | We take the mice, map and identify the genes affected and analyse the phenotype |
Collaborator Contribution | screening of mice for chemically induced mutant eye phenotypesidentification of mutant mouse strains, and generation of mutant mouse models |
Impact | PMID: 20943750 PMID: 20056676 PMID: 18765564 PMID: 16825286 PMID: 24809698 PMID: 23902802 PMID: 23633653 PMID: 23902802 PMID: 24809698 PMID: 25179226 PMID: 25736793 PMID: 26542706 PMID: 27534441 PMID: 30478029 other papers pre 2006 other papers in preparation |
Description | Headon |
Organisation | University of Edinburgh |
Department | The Roslin Institute |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | collaboration on idenfication of melanocyte stem cell in skin |
Collaborator Contribution | provision of transgenic mice analysis of data |
Impact | publication PMID:25847135 |
Start Year | 2014 |
Description | MRC Mouse Network |
Organisation | Cardiff University |
Department | School of Optometry and Vision Sciences |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | identification of genes to knock out in International Mouse Phenotyping Consortium |
Collaborator Contribution | discussion on gene targets. Production of KO mice |
Impact | KO mice produced |
Start Year | 2012 |
Description | MRC Mouse Network |
Organisation | Medical Research Council (MRC) |
Department | The Mary Lyon Centre |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | identification of genes to knock out in International Mouse Phenotyping Consortium |
Collaborator Contribution | discussion on gene targets. Production of KO mice |
Impact | KO mice produced |
Start Year | 2012 |
Description | Mitchison |
Organisation | University College London |
Department | Institute of Child Health |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | functional analysis of a ciliopathy gene |
Collaborator Contribution | supply of patient data and material |
Impact | student project publication PMID:25232951 |
Start Year | 2012 |
Description | Sanger IMPC |
Organisation | The Wellcome Trust Sanger Institute |
Country | United Kingdom |
Sector | Charity/Non Profit |
PI Contribution | analysis of mouse mutations |
Collaborator Contribution | provision of KO mice |
Impact | publications PMID:25736793 PMID:25356849 |
Start Year | 2010 |
Description | Sheridan |
Organisation | University of Leeds |
Department | Leeds Institute of Molecular Medicine |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | functional characterisation of a ciliopathy gene |
Collaborator Contribution | supply of patient data and material |
Impact | student project publication PMID:25232951 |
Start Year | 2012 |
Description | Simon John |
Organisation | The Jackson Laboratory |
Country | United States |
Sector | Charity/Non Profit |
PI Contribution | supplied mice with mutation probably resulting in glaucoma |
Collaborator Contribution | demonstration of raised intraocular pressure; a technique not available in UK. |
Impact | publication PMID:24809698 |
Start Year | 2007 |
Description | Tenesa/Bunger |
Organisation | Scotland's Rural College |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | experimental planning generation of data |
Collaborator Contribution | experimental planning analysis of data |
Impact | ongoing experiments |
Start Year | 2013 |
Description | Tenesa/Bunger |
Organisation | University of Edinburgh |
Department | The Roslin Institute |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | experimental planning generation of data |
Collaborator Contribution | experimental planning analysis of data |
Impact | ongoing experiments |
Start Year | 2013 |
Description | Yates maths |
Organisation | University of Bath |
Department | Department of Mathematical Sciences |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | provided biological data |
Collaborator Contribution | produced mathematical models |
Impact | publication PMID:26732977 multidisciplinary: mathematics and developmental biology |
Start Year | 2012 |
Description | cilia: Jarman |
Organisation | University of Edinburgh |
Department | Centre for Integrative Physiology |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | analysis of mouse mutant phenotypes and mouse cells |
Collaborator Contribution | gene identification in Drosophila |
Impact | two student projects publications PMID:25232951 PMID:24415959 |
Start Year | 2009 |
Description | mouse skin and hair mutations |
Organisation | MRC Harwell |
Department | MRC Mammalian Genetics Unit |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | identification and characterisation of mutant genes affecting hair development |
Collaborator Contribution | identification and supply of mutant mice with skin and hair defects |
Impact | Impact has been "this collaboration has meant we have begun working on a number of interesting mouse mutations which inform us about the developmental processes involved in hair and pigment formation. We have made significant progress in a number of areas" |
Description | Cafe Scientifique: Cockermouth |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Public/other audiences |
Results and Impact | talk on red hair genetics to general public |
Year(s) Of Engagement Activity | 2015 |
Description | Debating Matters |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | Yes |
Geographic Reach | Regional |
Primary Audience | Schools |
Results and Impact | discussion on scientific and non-scientific topics invitation to participate again |
Year(s) Of Engagement Activity | 2012 |
Description | Doors Open Day |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Public/other audiences |
Results and Impact | A presentation of our work on hair colour for visitors to the Institute's Doors Open Day |
Year(s) Of Engagement Activity | 2018 |
Description | HO Press briefing 2013 |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Media (as a channel to the public) |
Results and Impact | part of panel media briefing on Home Office statistics on use of animals for 2012 newspaper and website coverage |
Year(s) Of Engagement Activity | 2013 |
Description | Inaugural Lecture |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Public/other audiences |
Results and Impact | Inaugural lecture to an audience of general public and including numerous studetns from local schools |
Year(s) Of Engagement Activity | 2018 |
Description | Irish Radio |
Form Of Engagement Activity | A broadcast e.g. TV/radio/film/podcast (other than news/press) |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | live radio interview on Newstalk on National Radio of Ireland on our publication on hair colour genetics |
Year(s) Of Engagement Activity | 2018 |
Description | NC3Rs prize reception |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Professional Practitioners |
Results and Impact | reception associated with NC3Rs prize award |
Year(s) Of Engagement Activity | 2015,2016,2017 |
Description | Naked Scientist |
Form Of Engagement Activity | A broadcast e.g. TV/radio/film/podcast (other than news/press) |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | An interview for the NAked Scientist radio programme and podcast about our publication on hair colour genetics |
Year(s) Of Engagement Activity | 2018 |
Description | Newspaper coverage |
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 | Public/other audiences |
Results and Impact | 115 newspaper articles in response to press release about our publication on hair colour genetics |
Year(s) Of Engagement Activity | 2018,2019 |
Description | Radio NZ |
Form Of Engagement Activity | A broadcast e.g. TV/radio/film/podcast (other than news/press) |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Public/other audiences |
Results and Impact | Radio interview with New Zealand Radio on our publication on hair colour genetics |
Year(s) Of Engagement Activity | 2018 |
Description | TV interview |
Form Of Engagement Activity | A broadcast e.g. TV/radio/film/podcast (other than news/press) |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Public/other audiences |
Results and Impact | TV news interview about our publication on hair colour genetics |
Year(s) Of Engagement Activity | 2018 |
Description | Talk Radio |
Form Of Engagement Activity | A broadcast e.g. TV/radio/film/podcast (other than news/press) |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Public/other audiences |
Results and Impact | live radio interview on TalkRadio on our publication on hair colour genetics |
Year(s) Of Engagement Activity | 2019 |
Description | Twitter hair colour |
Form Of Engagement Activity | Engagement focused website, blog or social media channel |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | 526 twitter responses to newspaper reports on our publication on hair colour genetics |
Year(s) Of Engagement Activity | 2018,2019 |
Description | animal transport interview |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Public/other audiences |
Results and Impact | interview for BBC Radio 4 about the impact of the ban by ferry companies on carrying research animals press awareness |
Year(s) Of Engagement Activity | 2012 |
Description | black and white |
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 | Public/other audiences |
Results and Impact | press release on our Nature Communications paper. It was picked up by many newspapers in the UK and internationally. |
Year(s) Of Engagement Activity | 2016 |
URL | http://www.hgu.mrc.ac.uk/news_section/news_1.2016.html |
Description | red hair grant |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Public/other audiences |
Results and Impact | newspaper report on BBSRC grant award to study red hair genetics |
Year(s) Of Engagement Activity | 2017 |