Molecular, cellular and physiological basis of early onset hearing impairment

Lead Research Organisation: The Wellcome Trust Sanger Institute
Department Name: Research Directorate

Abstract

Human hearing impairment has many causes. Noise, drugs and infections can damage hearing, and many different genes (probably several hundred) can be involved. Interactions between genes and environment are likely to contribute to progressive hearing loss. We use a genetic approach to understand the molecular basis of auditory function and pathology, using the mouse as a model. The mouse has a typical mammalian cochlea very similar to that of humans, good DNA sequence resources, and many suitable mutants available for study. Mouse mutants with hearing and/or balance problems will be investigated, as balance anomalies are simple to detect and often are associated with deafness. The mutated gene will be identified in each case, and we shall screen the human version of each mouse deafness gene for mutations in affected families. Each mouse mutant will be studied using a multidisciplinary approach including auditory electrophysiology, ultrastructural analysis, gene expression studies, and developmental investigations to link understanding of the molecular basis of the defect with cell, organ and whole animal function. An understanding of the molecular basis of deafness is an essential first step towards developing treatments.

Technical Summary

Hearing impairment is very common in humans, but it is also a very heterogeneous disorder, with a wide range of causes. For example, there are probably several hundred genes involved in deafness, any one of which can be mutated and cause deafness in an individual. This makes it difficult to study directly in humans. The long-term aim of the work described here is to develop medical treatments for hearing impairment to provide an alternative to the imperfect approaches of amplification and cochlear implantation presently available. Developing new approaches must build upon improved understanding of the causes of hearing impairment and accurate diagnosis. A genetic approach, using hearing-impaired mouse mutants, is adopted to identify the key molecules in the development and function of hearing. As we assemble more of the molecular components, we not only will facilitate the development of generic approaches to treatment, but also establish which are most commonly involved in deafness in the human population. Further work can then focus upon the most common causes of human deafness. In this proposal, I outline plans to build upon the current work of my group to a) investigate the molecular basis of the development of sensory patches in the inner ear, b) investigate the role of key molecules in hair cell development and function, c) use mutants we have studied with a broad range of specific defects to develop diagnostic tools for particular pathologies, and d) screen newly-generated mouse mutants for evidence of hearing and/or balance defects, characterise their pathology, and ask which of the genes involved are associated with deafness in humans.

Publications


10 25 50
Bergman JE (2010) Study of smell and reproductive organs in a mouse model for CHARGE syndrome. in European journal of human genetics : EJHG
Bosman EA (2013) Omi, a recessive mutation on chromosome 10, is a novel allele of Ostm1. in Mammalian genome : official journal of the International Mammalian Genome Society
Calvert JA (2011) A missense mutation in Fgfr1 causes ear and skull defects in hush puppy mice. in Mammalian genome : official journal of the International Mammalian Genome Society
Carlisle FA (2012) Specific expression of Kcna10, Pxn and Odf2 in the organ of Corti. in Gene expression patterns : GEP
 
Description Royal Society Grants Committee
Geographic Reach National 
Policy Influence Type Participation in a advisory committee
 
Description EUMODIC
Amount £2,000,000 (GBP)
Organisation European Commission (EC) 
Sector Public
Country European Union (EU)
Start 01/2007 
End 01/2012
 
Title New deaf mouse mutants 
Description The funding has contributed to the production of many new mouse mutants affecting genes thought to be involved in auditory development or function 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Year Produced 2009 
Provided To Others? Yes  
Impact These new mutants are in the early stages of study, but it looks as if many unexpected genes underlie deafness, while other genes previously thought to be good candidates do not in fact lead to deafness. Around 3% (9/313) of all genes screened so far are associated with hearing impairment, and additional genes are associated with supra-threshold anomalies that we are currently following up. 
 
Title Software and other support for ABR recordings 
Description We supply software that we developed for optimised recording and analysis of Auditory Brainstem Response measurements to assess hearing ability in mice. Also, we supply details of the equipment needed and we host visits by researchers wanting to set the system up in their own lab. 
Type Of Material Improvements to research infrastructure 
Year Produced 2009 
Provided To Others? Yes  
Impact The ABR screen using this method has been adopted by the International Mouse Phenotyping Consortium and new data from targeted mouse mutants will emerge to add to our own screening data currently from over 600 new mutant lines, all available on the Sanger Institute Mouse portal 
 
Description Analysis of Synaptojanin2 mutant mouse 
Organisation University of Sheffield
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution We generated the derived tm1b allele from the original tm1a mutation, carried out ABRs, DPOAEs, expression studies, scanning electron microscopy, confocal imaging of innervation of hair cells, and characterisation of the effects of the allele on expression levels.
Collaborator Contribution Single hair cell recordings.
Impact So far a chapter in the student's thesis which is being adapted to form the basis of a publication.
Start Year 2014
 
Description Bioinformatic analysis of microarray data 
Organisation European Molecular Biology Laboratory (EMBL)
Department European Bioinformatics Institute (EBI)
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution We have generated the microarray data and carried out the remaining experiments required for each study, and contributed to the design, conduct, analysis and writing up of the work.
Collaborator Contribution Our collaborators have analysed out microarray data and provided descriptions and analyses of the results and contributed to the interpretation and writing up of the data.
Impact 19363478
Start Year 2008
 
Description Catweasel mutant mice 
Organisation Helmholtz Association of German Research Centres
Department German Research Centre for Environmental Health
Country Germany, Federal Republic of 
Sector Public 
PI Contribution We carried out all of the experimental work on these mutants after their initial discovery, including identification of the mutation and phenotypic characterisation. We designed, conducted, analysed and wrote up the work.
Collaborator Contribution Our collaborators carried out the initial screen of offspring from ENU-mutagenised males to detect new hearing or balance-impaired mouse mutants.
Impact 19389353
 
Description Chinese deaf children 
Organisation Chongqing University
Country China, People's Republic of 
Sector Academic/University 
PI Contribution We have proposed candidate genes for involvement in deafness from our mouse studies, and our collaborators included these genes in their targeted pulldown design followed by sequencing of DNA samples from affected children. We have followed up by further analysis of the specific mutations discovered associated with deafness
Collaborator Contribution See above. The Chinese collaborators recruited a very large sample of deaf children for DNA analysis, carried out the pulldown and sequencing, and followed up by looking at parents.
Impact The first joint paper was published this year, Bunillo et al. in EMBO Molecular Medicine.
Start Year 2011
 
Description Emx2 in pituitary gland 
Organisation University of Michigan
Country United States of America 
Sector Academic/University 
PI Contribution Our contribution was to provide genotyped, embedded and sectioned material of Emx2 mutants and littermate controls for analysis by our collaborators. We contributed to the design of the relevant part of the work, the conduct, and the writing up of the work.
Collaborator Contribution Our collaborators carried out the majority of the research described.
Impact 19407506
Start Year 2007
 
Description Functional analysis of Mir96 mutant hair cells 
Organisation Faculty of Science
Department Department of Biomedical Science
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution We have contributed to the collection of experimental data and to the design, conduct, analysis and writing up of the work.
Collaborator Contribution Our collaborators have contributed to the collection of experimental data and the analysis, interpretation and writing up of the findings.
Impact 21245307
Start Year 2008
 
Description Functional analysis of Tmc1 mouse mutants 
Organisation University of Sussex
Department School of Life Sciences Sussex
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution We analysed the ultrastructure of the sensory hair cells in mutants with Tmc1 mutations and contributed to the design, conduct, analysis and writing up of the work.
Collaborator Contribution Our collaborators carried out a detailed study of single hair cell physiology in mutants with Tmc1 mutatons, and contributed to the design, conduct, analysis and writing up of the work.
Impact 16627570
 
Description Functional analysis of a new Atp2b2 mutation, oblivion. 
Organisation Venetian Institute of Molecular Medicine (VIMM)
Country Italy, Italian Republic 
Sector Academic/University 
PI Contribution We identified the mutation in the Atp2b2 gene by positional cloning, characterised the gross electrophysiological and ultrastructural phenotype of the ear in the mutant mice, and contributed to the design, conduct, analysis and writing up of the work.
Collaborator Contribution Our collaborators have undertaken a detailed electrophysiological analysis of the effects of a new mutation in the Atp2b2 gene, and contributed to the design, conduct, analysis and writing up of the work.
Impact 18974863
 
Description Genotype/phenotype analysis in Usher syndrome 
Organisation University College London (UCL)
Department Institute of Ophthalmology UCL
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution We provided the sequencing of the patient DNA and the initial sequence analysis and contributed to the design, conduct, analysis and writing up of the work.
Collaborator Contribution Our collaborators carried out the detailed clinical assessments of the patients in this study and contributed to the design, conduct, analysis and writing up of the work.
Impact 21487335
Start Year 2007
 
Description Hearing in the Cx30 T5M mutant 
Organisation Venetian Institute of Molecular Medicine (VIMM)
Country Italy, Italian Republic 
Sector Academic/University 
PI Contribution We established our own in house breeding colony of these mutants, used offspring of all genotypes to measure endocochlear potential in the cochlea, and contributed to writing the manuscript.
Collaborator Contribution Our collaborators carried out experimental work on the mutant mice and contributed to the design, materials, conduct, analysis and writing up of the work.
Impact 20858605
Start Year 2009
 
Description Hearing loss in the 101/H mouse strain 
Organisation Pasteur Institute, Paris
Country France, French Republic 
Sector Academic/University 
PI Contribution We carried out the detailed phenotypic analysis of the 101/H strain and outcrossed and backcrossed mice, and contributed to the design, conduct, analysis and writing up of the work.
Collaborator Contribution Our collaborators bred and provided a series of outcrossed and backcrossed mice from the 101/H and wild-derived strains of mice and carried out the genetic analysis of DNA samples from them to detect quantitative trait loci, and contributed to the design, conduct, analysis and writing up of the work.
Impact 16897347
 
Description Lipidomic analysis of the Acsl4 mouse cochlea 
Organisation Queen Mary University of London (QMUL)
Department Queen Mary College
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution We collected the samples and genotyped them, and provided all the background data that led to the hypothesis that lipid metabolism might be abnormal.
Collaborator Contribution They carried out the processing of the sample, mass spectrometry and analysis of the findings presented in a report.
Impact We have pilot data and are continuing the analysis.
Start Year 2015
 
Description Mir96 in human and mouse deafness 
Organisation Hospital Ramón y Cajal
Country Spain, Kingdom of 
Sector Hospitals 
PI Contribution We have contributed all of the work on the mouse mutation in Mir96 including identification of the gene involved as a microRNA and characterisation of the phenotype of the mouse.
Collaborator Contribution Our collaborators have contributed to our combined effort to identify the mutations responsible for progressive hearing loss in mice and humans, in particular carrying out all of the work on human families.
Impact 19363479; 19363478
Start Year 2006
 
Description Modelling of a new Isl1 mutation 
Organisation European Molecular Biology Laboratory (EMBL)
Department European Bioinformatics Institute (EBI)
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution We discovered the mutation, established the phenotype, and designed the experiments, carried out the experimental work, analysed the results and wrote the paper.
Collaborator Contribution Our collaborator modelled the new mutation in Isl1 and its probable effect on protein interactions and drafted the text describing this for the publication
Impact 21936904
Start Year 2011
 
Description Phenotypes of Tbx1 and Chd7 mouse mutants 
Organisation University College London (UCL)
Department UCL Institute of Child Health
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution We prepared the inner ears for paint-filling and analysed the malformations, and contributed to writing the relevant parts of the paper.
Collaborator Contribution Dr Scambler and his colleagues carried out the mouse breeding experiments and detailed analysis of head development, and provided fixed inner ears for us to examine and analyse.
Impact 19855134
Start Year 2008
 
Description Role of Emx2 in ear development 
Organisation Faculty of Science
Department Department of Biomedical Science
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution We carried out experimental work on the role of Emx2 in the development of the organ of Corti. We contributed to the design, materials, conduct, analysis and writing up of the work.
Collaborator Contribution Our collaborators carried out part of the experimental work and contributed to the design, materials, conduct, analysis and writing up of the work.
Impact 20152827
 
Description Role of MYO7A in retinal function 
Organisation University of California, Los Angeles (UCLA)
Department Jules Stein Eye Institute UCLA
Country United States of America 
Sector Academic/University 
PI Contribution We carried out the initial study of the effect of light on retinal structure and function in mice with Myo7a mutations and contributed to the design, conduct, analysis and writing up of the work.
Collaborator Contribution Our collaborators carried out the follow-up analysis of Myo7a in retinal function in the eye and contributed to the design, conduct, analysis and writing up of the work.
Impact 21493626
 
Description Role of Wnt5a in ear development 
Organisation Emory University
Department School of Medicine Emory
Country United States of America 
Sector Academic/University 
PI Contribution We have carried out a scanning electron microscopic analysis of the organ of Corti in Wnt5a mutant mouse samples from our collaborator and contributed to the design, conduct, analysis and writing up of the work.
Collaborator Contribution Our collaborators have carried out a detailed analysis of the development of the organ of Corti in the Wnt5a mouse mutant and contributed to the design, conduct, analysis and writing up of the work.
Impact 17433286
Start Year 2006
 
Description Role of myosin VI in deafness 
Organisation Tel Aviv University (TAU)
Country Israel, State of 
Sector Academic/University 
PI Contribution We have analysed the ultrastructure of the Myo6 mutant mice, and contributed to the planning, conduct, analysis and writing up of the relevant parts of the work.
Collaborator Contribution Our collaborators have carried out research on the functional results of a new mutation in the Myo6 gene causing deafness in the mouse.
Impact 18833301
 
Description Role of twinfilin in hair cells 
Organisation University of Helsinki (Helsingin yliopisto)
Country Finland, Republic of 
Sector Academic/University 
PI Contribution We carried out experimental work on the role of twinfilin in the development of stereocilia bundles on hair cells. We contributed to the design, materials, conduct, analysis and writing up of the work.
Collaborator Contribution Our collaborators provided essential materials for the analysis of the role of twinfilin in hair cell development and carried out some of the exeriments in Helsinki. They contributed to the design, conduct, analysis and writing up of the work.
Impact 19774077
Start Year 2007
 
Description Smell and reproductive organs in Chd7 mice 
Organisation University of Groningen
Department University Medical Center Gronigen
Country Netherlands, Kingdom of the 
Sector Hospitals 
PI Contribution We carried out all the work jointly with the clinician student from Groningen in my laboratory. We contributed to the design, materials, conduct, analysis and writing up of the work.
Collaborator Contribution Our collaborators sent a clinician student to my laboratory to carry out basic mouse research and contributed to the design, analysis and writing up of the work.
Impact 19809474
Start Year 2007
 
Description Study of Ildr4 mutation 
Organisation National Institutes of Health (NIH)
Department National Institute on Deafness and Other Communication Disorders (NIDCD)
Country United States of America 
Sector Public 
PI Contribution Phalloidin labelling to examine hair bundles in the mutants and littermate controls. Endocochlear potential measurements and ABR analysis. Analysing and writing up relevant parts of the publication.
Collaborator Contribution The partners carried out the rest of the analyses published.
Impact A publication was the result.
Start Year 2014
 
Description Study of retinal defects in mouse mutants 
Organisation University of California, Los Angeles (UCLA)
Department School of Medicine UCLA
Country United States of America 
Sector Academic/University 
PI Contribution We have bred, genotyped and fixed eyes from mutant mice of various types to provide to our collaborators for further analysis, and contributed to the design, conduct, analysis and writing up of the work.
Collaborator Contribution Our collaborators have carried out the detailed analysis of samples of eyes from mutant mice and contributed to the design, conduct, analysis and writing up of the work.
Impact 18463160
 
Description Ultrastructure of the whirler mutant hair cells 
Organisation University of East Anglia
Department School of Biological Sciences UEA
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution We provided fixed and genotyped samples and also carried out the detailed scanning electron microscopic analysis, and contributed to the design, conduct, analysis and writing up of the work.
Collaborator Contribution Our collaborator carried out a detailed transmission electron microscopic analysis of whirler mutant hair cells, and contributed to the design, conduct, analysis and writing up of the work.
Impact 17326148
 
Title Software for recording and analysing auditory responses 
Description Software for recording and analysing auditory responses 
Type Of Technology Software 
Year Produced 2008 
Impact We have distributed this software free of charge to around ten other laboratories working on recording auditory responses from mutant mice, around the world. 
 
Description Brain prize talk 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact I presented a talk at the Brain Prize ceremony, attended by many Danish lay people, politicians, health researchers, etc.

Requests for further outreach talks in Denmark
Year(s) Of Engagement Activity 2012
 
Description ECNP plenary talk 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Health professionals
Results and Impact Over 1000 clinical psychologists attended

Not known yet
Year(s) Of Engagement Activity 2013
 
Description Interview 
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 Media (as a channel to the public)
Results and Impact Interview and article with The Scientist magazine
Year(s) Of Engagement Activity 2015
 
Description Interview for Naked Scientist 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact Not known yet
Year(s) Of Engagement Activity 2013
 
Description Interview for journal article 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact I was interviewed for an on-line video and/or journal frontpiece article for four articles.

Nothing known
Year(s) Of Engagement Activity 2010,2011,2012
 
Description Interview on BBC TV programme See Hear 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Media (as a channel to the public)
Results and Impact An extended interview was broadcast, resulting in a number of positive comments about the content and manner of the interview.

None known
Year(s) Of Engagement Activity 2010
 
Description Public talk in Denmark 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Much interest from the 500 members of the public afterwards - over an hour answering questions after talk.

Not known yet
Year(s) Of Engagement Activity 2013
 
Description Radio interview 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact Not known yet
Year(s) Of Engagement Activity 2013
 
Description Telephone interviews about research 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact Talking about my work on deafness using mouse models to the media.

Nothing known
Year(s) Of Engagement Activity 2006,2007,2008,2009,2010