Genetic models of human disease
Lead Research Organisation:
MRC Human Genetics Unit
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.
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.
Organisations
- MRC Human Genetics Unit, United Kingdom (Lead Research Organisation)
- University of Edinburgh, United Kingdom (Collaboration)
- MRC Harwell, United Kingdom (Collaboration)
- University of Aberdeen, United Kingdom (Collaboration)
- Cardiff University, United Kingdom (Collaboration)
- The Jackson Laboratory (Collaboration)
- Medical Research Council (Collaboration)
- National Institute for Physiological Sciences (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

Church DM
(2009)
Lineage-specific biology revealed by a finished genome assembly of the mouse.
in PLoS biology

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

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

Gautier P
(2008)
Expression of the fras1/frem gene family during zebrafish development and fin morphogenesis.
in Developmental dynamics : an official publication of the American Association of Anatomists

Hall EA
(2013)
Acute versus chronic loss of mammalian Azi1/Cep131 results in distinct ciliary phenotypes.
in PLoS genetics

Handley MT
(2015)
Warburg Micro syndrome is caused by RAB18 deficiency or dysregulation.
in Open biology

Handley MT
(2014)
Loss of ALDH18A1 function is associated with a cellular lipid droplet phenotype suggesting a link between autosomal recessive cutis laxa type 3A and Warburg Micro syndrome.
in Molecular genetics & genomic medicine
Description | Chair, RSCPA Resource Sharing Working Group |
Geographic Reach | National |
Policy Influence Type | Membership of a guidance committee |
Impact | guidelines for sharing and archiving of genetically altered mice; These guidelines will be published soon. Endorsed by MRC, BBSCR, Wellcome Trust, CRUK, NC3Rs |
Description | Imperial College committee |
Geographic Reach | National |
Policy Influence Type | Participation in advisory committee |
Impact | Universities are improving animal care conditions |
Description | Infrafrontier 2018 |
Geographic Reach | Europe |
Policy Influence Type | Participation in a advisory committee |
Description | MRC Data Sharing |
Geographic Reach | National |
Policy Influence Type | Membership of a guideline committee |
Description | MRC Genetically Modified Mouse Welfare Assessment Group |
Geographic Reach | National |
Policy Influence Type | Membership of a guidance committee |
Impact | guidelines for rational analysis of impact of genetic modification on mouse welfare; publication of guidelines |
Description | Participation in discussions on hybrid embryos in advance of proposed Embryology Bill |
Geographic Reach | National |
Policy Influence Type | Participation in a national consultation |
Impact | advice to government on proposed Embryology Bill. ; Bill as finally formulated conformed with MRC's suggestions with respect to hybrid embryos |
Description | Scientific Advisory Group to PRIME (Priorities in Mouse Genomics Research in Europe) |
Geographic Reach | Multiple continents/international |
Policy Influence Type | Participation in advisory committee |
Impact | formulation of policy and proposals to fund mouse genetics and genomics in Europe; sustained funding from EC to mouse genetics |
Description | Transgenic mouse regulation |
Geographic Reach | National |
Policy Influence Type | Participation in a national consultation |
Impact | Home Office are considering changes to the regulations regarding reporting of transgenic mouse experiments |
Description | UK DNA Bank Steering Committee |
Geographic Reach | National |
Policy Influence Type | Participation in advisory committee |
Impact | advisory board and subsequent review of MRC UK DNA Bank; priorities and scientific direction for UK DNA Bank |
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 | EUMODIC The European Mouse Disease Clinic: A distributed phenotyping resource for studying human disease (12m euros across 18 participants) |
Amount | £130,000 (GBP) |
Funding ID | 37188 |
Organisation | European Commission |
Sector | Public |
Country | European Union (EU) |
Start | 02/2007 |
End | 01/2012 |
Title | Col4a |
Description | Several mouse lines with missense mutations in the Col4a1 gene. These are the first models of a number of vascular diseases |
Type Of Material | Model of mechanisms or symptoms - mammalian in vivo |
Year Produced | 2006 |
Provided To Others? | Yes |
Impact | PMID: 20056676 Identification of human families with similar mutations. Young researcher is using these mice as the basis of his first grant applications |
URL | http://europepmc.org/abstract/MED/20056676 |
Title | Corin |
Description | mice mutant in the corin gene |
Type Of Material | Model of mechanisms or symptoms - mammalian in vivo |
Provided To Others? | No |
Impact | understanding of the role of corin in regulating mammalian pigmentation |
Title | Dilp2 |
Description | mouse model for human disease in which filamin A is mutated |
Type Of Material | Model of mechanisms or symptoms - mammalian in vivo |
Year Produced | 2007 |
Provided To Others? | Yes |
Impact | this was the first mouse model of this disease PMID: 16825286 our publication others have publications in preperation |
URL | http://europepmc.org/abstract/MED/16825286 |
Title | GENA40 |
Description | mice with a gain of function mutation in the Gnas gene |
Type Of Material | Model of mechanisms or symptoms - mammalian in vivo |
Provided To Others? | No |
Impact | understanding of the mechanisim of signalling of Mc1r |
Title | Pax2 |
Description | mouse with a partial loss of function of the Pax2 gene |
Type Of Material | Model of mechanisms or symptoms - mammalian in vivo |
Provided To Others? | No |
Impact | PMID: 20943750 |
URL | http://europepmc.org/abstract/MED/20943750 |
Title | Pde6b |
Description | several mouse lines with mutation in Pde6b. These are models for autosomal recessive retinitis pigmentosa in humans |
Type Of Material | Model of mechanisms or symptoms - mammalian in vivo |
Year Produced | 2006 |
Provided To Others? | Yes |
Impact | some of the lines have slower retinal degeration than the previous models. This allows a therapeutic window |
Title | Tyrp1 deletion |
Description | sequence of the mouse genome. We played some part in the generation and analysis of the mouse genome sequence. |
Type Of Material | Biological samples |
Year Produced | 2006 |
Provided To Others? | Yes |
Impact | an almost universal tool for mouse genetics |
Title | Zdhhc21 antibody |
Description | antibody against mouse protein, Zdhhc21 |
Type Of Material | Antibody |
Year Produced | 2009 |
Provided To Others? | Yes |
Impact | PMID: 19956733 |
URL | http://europepmc.org/abstract/MED/19956733 |
Description | Aligianis |
Organisation | Medical Research Council (MRC) |
Department | MRC Human Genetics Unit |
Country | United Kingdom |
Sector | Public |
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 | Public |
PI Contribution | analysed mouse mutant embryos |
Collaborator Contribution | led project |
Impact | paper PMID: 22579044 |
Start Year | 2011 |
Description | Eumodic |
Organisation | MRC Harwell |
Department | MRC Mammalian Genetics Unit |
Country | United Kingdom |
Sector | Public |
PI Contribution | generation of screening protocols for the examination of mutant mice |
Collaborator Contribution | identification and supply of useful mouse models of disease |
Impact | identification of mutant mice on which we are now working PMID: 19933761 |
Start Year | 2007 |
Description | Fukata |
Organisation | National Institute for Physiological Sciences |
Country | Japan |
Sector | Academic/University |
PI Contribution | We identified the mutant gene and characterised the phenotype |
Collaborator Contribution | Collaborators carried out experiments to assay the function of a mutant gene we discovered |
Impact | PMID: 19956733 |
Start Year | 2008 |
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 | Public |
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 | Public |
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 | 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 | Shen |
Organisation | University of Aberdeen |
Department | Institute of Medical Sciences |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | We assessed the visual function of their mouse model |
Collaborator Contribution | They made a transgenic mouse model |
Impact | PMID: 19596361 |
Start Year | 2008 |
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 | mouse skin and hair mutations |
Organisation | MRC Harwell |
Department | MRC Mammalian Genetics Unit |
Country | United Kingdom |
Sector | Public |
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 | British Festival of Science |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | Yes |
Geographic Reach | National |
Primary Audience | Public/other audiences |
Results and Impact | 50-100 members of the public participated in a discussion about human:animal mosaics interview posted on websites |
Year(s) Of Engagement Activity | 2010 |
Description | British Festival of Science |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Public/other audiences |
Results and Impact | gave a talk, along with 2 others, on putting human genes into cells as part of an Academy of Medical Sciences sponsored session. Audience of about 50, mostly school and college students press coverage of the event which was a launch of a AcadMedSci report. |
Year(s) Of Engagement Activity | 2010 |
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 | School visit: Plockton |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Schools |
Results and Impact | Emma Hall, a student in the group, was researcher in residence at Plockton High School positive feedback from pupils and teachers |
Year(s) Of Engagement Activity | 2009 |