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.

Publications

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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

 
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