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.

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

10 25 50
 
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 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 Academic/University
Country United Kingdom
Start 09/2013 
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 10/2017 
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 
 
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 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 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 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 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