Archive Page: Genetics of deafness

The Genetics of deafness group moved to King's College London in October 2012. The team continues to work under Karen Steel, Professor of Sensory Function at the Wolfson Centre for Age-Related Diseases. We are maintaining this page as a historical record of the group's activities at the Sanger Institute. For latest information about the group's research, please visit King's College London.

The Genetics of deafness group investigated genes involved in hearing and balance disorders.

Hearing impairment can result from environmental or genetic factors and the team, headed by Karen Steel, aimed to identify the genes associated with deafness and to determine their function. They studied a collection of lines of mice each with a single mutated gene leading to abnormal development of the ear and hearing impairment. In addition the team analysed mice with progressive hearing loss to determine which genes may be involved. The long-term aim is to transfer this knowledge to applications, such as development of treatments, in humans.

[Graham Froggatt, Wellcome Trust Sanger Institute]

Background

Hearing impairment is very common in human populations, but it is a very heterogeneous disorder, with a wide range of causes. Environmental insults like noise, drugs and infections can damage hearing, but there is also a strong genetic component to hearing impairment, including single gene mutations, polygenic contributions, and gene variants that make carriers especially sensitive to environmental damage.

It is difficult to disentangle the causes of hearing impairment directly in humans, particularly as it seems that there may be several hundred different genes that can be involved. Thus, we used the mouse as a model for human deafness as we could isolate and precisely control both the genome and the environment of a mouse.

Research

Our aims

The team screened newly-generated mouse mutants to discover new genes affecting hearing and balance and to understand the pathological mechanisms underlying deafness. The screen provided a rich resource of mutants for further analysis of the molecular, cellular and physiological basis of hearing and balance disorders. The long-term aim was to transfer this knowledge to applications, such as development of treatments, in humans.

Our approach

Our approach is to discover new genes involved in deafness by looking for this phenotype in newly-generated mutant mice. This involves screening mice with new induced mutations for deafness, then identifying the gene affected. To get an insight into the basic biological mechanisms underlying hearing impairment, we use approaches that can be carried out only in an animal model, such as developmental studies, detailed electrophysiological measurements of cochlear function, genetic manipulation and high-quality ultrastructural studies.

Screening for new genes involved in hearing and balance defects

The Sanger Institute is creating an extensive collection of new mouse mutants, with the ultimate goal of having a mutation in every gene in the mouse genome (see the Mouse genetics project). We screened all of these mutants as they became available to assess whether the mutation affects hearing, using a rapid statistical ABR (auditory brainstem response) approach, and balance, using a screen for specific behaviours associated with vestibular defects. Mutants with even mild hearing impairments could be detected using this approach. Mutants were analysed further using our standard battery of techniques, including examination of the inner and middle ears for signs of malformations and scanning electron microscopy of the organ of Corti, as a first pass examination, and particularly interesting mutants were studied further by the group to address specific questions as appropriate to the phenotype.

Development of sensory patches in the inner ear

We had a number of partly-characterised new mouse mutants that showed abnormal development of sensory patches within the inner ear, including at least two that show no sign of development of these patches at all. In some cases we knew the affected gene, but in others we were in the late stages of positional cloning and it seemed likely that a novel gene was involved. We analysed these mutants in order to define the role of the mutated genes in the cascade of gene activity required for the specification and further development of the sensory patches. This information is useful in attempts to stimulate the regeneration of sensory patches as a treatment for deafness, as well as providing tools to address basic developmental biology questions.

Molecular basis of hair cell development and function

Several of the mutants that we had studied previously showed primary defects of the stereocilia bundle at the top of sensory hair cells. This bundle is the site of transduction of mechanical energy into electrical activity within the hair cell, so it is critical to auditory function and is of great scientific interest. We had a reasonably good understanding of the role of some of the genes involved in stereocilia bundle development and function for example Myo7a, but other mutants were only partly characterised. We systematically to analysde the development of the bundle in these mutants using high resolution electron microscopy, ultrastructural localisation of the proteins involved, and measurement of electrophysiological responses in whole mouse as well as single hair cell preparations. We started with existing mutants, and included new mutants with hair cell defects as they were revealed by our screening programme.

Late-onset progressive hearing loss

Age-related hearing loss affects a very large proportion of the human population, but we have few clues to the reasons. However, in some cases we know that a single gene is involved, and heritability in the wider population is around 50 per cent indicating a significant genetic contribution. We had several mouse mutants with progressive hearing loss and we sought to identify the genes involved to provide candidates for investigation in affected humans. We studied the role of these genes in normal development and function of the inner ear, by expression analysis and by correlating physiological function with ultrastructural appearance of the various components of the cochlear duct. The influence of known modifier genes on the deterioration in cochlear function was investigated, and we asked if hearing loss could be prevented by attempting to prevent hair cell degeneration.

International collaborations

The team was a partner in the European Mouse Disease Clinic (EUMODIC) which aims to analyse 500 mutant mouse lines and screen them for features of diseases of interest. The mouse mutants undergo a primary analysis by a broad-based, high-throughput phenotyping screen. Lines with specific features are studied further by secondary phenotyping groups with expertise in the relevant area. The team was also a member of the EuroHear Consortium, a major international collaboration that aims to understand the mechanisms involved in normal hearing and the genetic and molecular mechanisms underlying hearing impairment. In addition, the team collaborated widely with other groups with similar interests in studying the molecular basis of deafness in mice and in humans.

Selected publications

  • An ENU-induced mutation of miR-96 associated with progressive hearing loss in mice.

    Lewis MA, Quint E, Glazier AM, Fuchs H, De Angelis MH, Langford C, van Dongen S, Abreu-Goodger C, Piipari M, Redshaw N, Dalmay T, Moreno-Pelayo MA, Enright AJ and Steel KP

    Nature genetics 2009;41;5;614-8

  • Mutations in the seed region of human miR-96 are responsible for nonsyndromic progressive hearing loss.

    Mencía A, Modamio-Høybjør S, Redshaw N, Morín M, Mayo-Merino F, Olavarrieta L, Aguirre LA, del Castillo I, Steel KP, Dalmay T, Moreno F and Moreno-Pelayo MA

    Nature genetics 2009;41;5;609-13

  • Presence of interstereocilial links in waltzer mutants suggests Cdh23 is not essential for tip link formation.

    Rzadzinska AK and Steel KP

    Neuroscience 2009;158;2;365-8

  • The novel mouse mutation Oblivion inactivates the PMCA2 pump and causes progressive hearing loss.

    Spiden SL, Bortolozzi M, Di Leva F, de Angelis MH, Fuchs H, Lim D, Ortolano S, Ingham NJ, Brini M, Carafoli E, Mammano F and Steel KP

    PLoS genetics 2008;4;10;e1000238

  • Usher syndromes due to MYO7A, PCDH15, USH2A or GPR98 mutations share retinal disease mechanism.

    Jacobson SG, Cideciyan AV, Aleman TS, Sumaroka A, Roman AJ, Gardner LM, Prosser HM, Mishra M, Bech-Hansen NT, Herrera W, Schwartz SB, Liu XZ, Kimberling WJ, Steel KP and Williams DS

    Human molecular genetics 2008;17;15;2405-15

  • Mosaic complementation demonstrates a regulatory role for myosin VIIa in actin dynamics of stereocilia.

    Prosser HM, Rzadzinska AK, Steel KP and Bradley A

    Molecular and cellular biology 2008;28;5;1702-12

  • A Myo6 mutation destroys coordination between the myosin heads, revealing new functions of myosin VI in the stereocilia of mammalian inner ear hair cells.

    Hertzano R, Shalit E, Rzadzinska AK, Dror AA, Song L, Ron U, Tan JT, Shitrit AS, Fuchs H, Hasson T, Ben-Tal N, Sweeney HL, de Angelis MH, Steel KP and Avraham KB

    PLoS genetics 2008;4;10;e1000207

  • The deaf mouse mutant whirler suggests a role for whirlin in actin filament dynamics and stereocilia development.

    Mogensen MM, Rzadzinska A and Steel KP

    Cell motility and the cytoskeleton 2007;64;7;496-508

  • Wnt5a functions in planar cell polarity regulation in mice.

    Qian D, Jones C, Rzadzinska A, Mark S, Zhang X, Steel KP, Dai X and Chen P

    Developmental biology 2007;306;1;121-33

  • A Sall4 mutant mouse model useful for studying the role of Sall4 in early embryonic development and organogenesis.

    Warren M, Wang W, Spiden S, Chen-Murchie D, Tannahill D, Steel KP and Bradley A

    Genesis (New York, N.Y. : 2000) 2007;45;1;51-8

  • Tmc1 is necessary for normal functional maturation and survival of inner and outer hair cells in the mouse cochlea.

    Marcotti W, Erven A, Johnson SL, Steel KP and Kros CJ

    The Journal of physiology 2006;574;Pt 3;677-98

  • Two quantitative trait loci affecting progressive hearing loss in 101/H mice.

    Mashimo T, Erven AE, Spiden SL, Guénet JL and Steel KP

    Mammalian genome : official journal of the International Mammalian Genome Society 2006;17;8;841-50

  • Multiple mutations in mouse Chd7 provide models for CHARGE syndrome.

    Bosman EA, Penn AC, Ambrose JC, Kettleborough R, Stemple DL and Steel KP

    Human molecular genetics 2005;14;22;3463-76

  • Myosin VI is required for normal retinal function.

    Kitamoto J, Libby RT, Gibbs D, Steel KP and Williams DS

    Experimental eye research 2005;81;1;116-20

  • Sox2 is required for sensory organ development in the mammalian inner ear.

    Kiernan AE, Pelling AL, Leung KK, Tang AS, Bell DM, Tease C, Lovell-Badge R, Steel KP and Cheah KS

    Nature 2005;434;7036;1031-5

Reviews & books

  • Genetics.

    Steel KP

    In: Scott-Brown's Otorhinolaryngology, Head and Neck Surgery, seventh edition. Hodder/Edward Arnold Publishers, London 2008

  • The ear.

    Spiden SL and Steel KP

    In: Embryos, genes and Birth Defects, eds P Ferretti, A Copp, C Tickle, G Moore. John Wiley, London. 2008;231-262

  • Characterising hearing in mice.

    Steel KP

    In: Standards of Mouse Model Phenotyping, eds M Hrabe de Angelis, P Chambon, SDM Brown. Wiley-VCH, Weinheim. 2006;1-14

  • Genetic and environmental influences on hearing impairment.

    Steel KP

    In: Genes and Common Diseases - Genetics in Modern Medicine, eds. A F Wright and N D Hastie, Cambridge University Press, Cambridge, 2005;505-515

  • Development of the mouse inner ear.

    Kiernan AE, Steel KP and Fekete DM

    In: Mouse Development, eds J Rossant and PPL Tam. Academic Press, San Diego. 2002;539-566

  • A genetic approach to understanding auditory function.

    Steel KP and Kros CJ

    Nature genetics 2001;27;2;143-9

  • Mice as models for human hereditary deafness.

    Steel KP, Erven A and Kiernan AE

    In: Springer Handbook of Auditory Research, Genetics and Auditory Disorders, eds BJ Keats, AN Popper and RR Fay. Springer, New York. 1995;247-296

Team

Team members

Morag Lewis
Visiting Scientist

Morag Lewis

- Visiting Scientist

I studied Biological Natural Sciences at the University of Cambridge, then spent a year doing the Diploma in Computer Science in the same place. However, I found I did prefer biology after all, and did a PhD in the Zoology Department, studying the evolution of the development of the bristles on the back of the malaria mosquito, Anopheles gambiae. After completing my PhD, I took a temporary job covering a postdoc's maternity leave in my current team; when she decided to stay at home with her daughter I was very happy to continue working here.

Research

Hearing loss is a common problem in the human population, and about half of all cases have a genetic basis. However, a large number of these genes have yet to be identified.

I am studying two mouse mutants which exhibit sensory hair cell degeneration, hearing impairment and balance defects. One has a mutation in microRNA96, which is expressed specifically in hair cells and regulates many genes. The other has a unique phenotype of degeneration in the inner hair cells only; the mutation has been mapped to a region on chromosome 5, but the gene responsible has not yet been identified.

References

  • miR-96 regulates the progression of differentiation in mammalian cochlear inner and outer hair cells.

    Kuhn S, Johnson SL, Furness DN, Chen J, Ingham N, Hilton JM, Steffes G, Lewis MA, Zampini V, Hackney CM, Masetto S, Holley MC, Steel KP and Marcotti W

    Department of Biomedical Science, University of Sheffield, Sheffield S10 2TN, United Kingdom.

    MicroRNAs (miRNAs) are small noncoding RNAs able to regulate a broad range of protein-coding genes involved in many biological processes. miR-96 is a sensory organ-specific miRNA expressed in the mammalian cochlea during development. Mutations in miR-96 cause nonsyndromic progressive hearing loss in humans and mice. The mouse mutant diminuendo has a single base change in the seed region of the Mir96 gene leading to widespread changes in the expression of many genes. We have used this mutant to explore the role of miR-96 in the maturation of the auditory organ. We found that the physiological development of mutant sensory hair cells is arrested at around the day of birth, before their biophysical differentiation into inner and outer hair cells. Moreover, maturation of the hair cell stereocilia bundle and remodelling of auditory nerve connections within the cochlea fail to occur in miR-96 mutants. We conclude that miR-96 regulates the progression of the physiological and morphological differentiation of cochlear hair cells and, as such, coordinates one of the most distinctive functional refinements of the mammalian auditory system.

    Funded by: Action on Hearing Loss: G41; Medical Research Council: G0300212, MC_QA137918; Wellcome Trust: 077189, 088719

    Proceedings of the National Academy of Sciences of the United States of America 2011;108;6;2355-60

  • MicroRNAs in mouse development and disease.

    Lewis MA and Steel KP

    Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK.

    MicroRNAs, small non-coding RNAs which act as repressors of target genes, were discovered in 1993, and since then have been shown to play important roles in the development of numerous systems. Consistent with this role, they are also implicated in the pathogenesis of multiple diseases. Here we review the involvement of microRNAs in mouse development and disease, with particular reference to deafness as an example.

    Funded by: Medical Research Council: G0300212, MC_QA137918; Wellcome Trust

    Seminars in cell & developmental biology 2010;21;7;774-80

  • An ENU-induced mutation of miR-96 associated with progressive hearing loss in mice.

    Lewis MA, Quint E, Glazier AM, Fuchs H, De Angelis MH, Langford C, van Dongen S, Abreu-Goodger C, Piipari M, Redshaw N, Dalmay T, Moreno-Pelayo MA, Enright AJ and Steel KP

    Wellcome Trust Sanger Institute, Hinxton, UK.

    Progressive hearing loss is common in the human population, but little is known about the molecular basis. We report a new N-ethyl-N-nitrosurea (ENU)-induced mouse mutant, diminuendo, with a single base change in the seed region of Mirn96. Heterozygotes show progressive loss of hearing and hair cell anomalies, whereas homozygotes have no cochlear responses. Most microRNAs are believed to downregulate target genes by binding to specific sites on their mRNAs, so mutation of the seed should lead to target gene upregulation. Microarray analysis revealed 96 transcripts with significantly altered expression in homozygotes; notably, Slc26a5, Ocm, Gfi1, Ptprq and Pitpnm1 were downregulated. Hypergeometric P-value analysis showed that hundreds of genes were upregulated in mutants. Different genes, with target sites complementary to the mutant seed, were downregulated. This is the first microRNA found associated with deafness, and diminuendo represents a model for understanding and potentially moderating progressive hair cell degeneration in hearing loss more generally.

    Funded by: Medical Research Council: G0300212, MC_QA137918; Wellcome Trust: 077189, 077198

    Nature genetics 2009;41;5;614-8

* quick link - http://q.sanger.ac.uk/gendeaf