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 use the mouse as a model for human deafness as we can isolate and precisely control both the genome and the environment of a mouse.

Research

Our aims

The team is screening newly-generated mouse mutants to discover new genes affecting hearing and balance and to understand the pathological mechanisms underlying deafness. The screen will provide a rich resource of mutants for further analysis of the molecular, cellular and physiological basis of hearing and balance disorders. The long-term aim is 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 programme). We screen all of these mutants as they become 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 can be detected using this approach. Mutants are 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 are studied further by the group to address specific questions as appropriate to the phenotype.

Development of sensory patches in the inner ear

We have a number of partly-characterised new mouse mutants that show 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 know the affected gene, but in others we are in the late stages of positional cloning and it seems likely that a novel gene will be involved. We plan to continue the analysis of 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 will be 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 have studied previously show 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 have 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 are only partly characterised so far. We plan systematically to analyse 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 shall start with existing mutants, and include new mutants with hair cell defects as they are 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 have several mouse mutants with progressive hearing loss and we plan to identify the genes involved to provide candidates for investigation in affected humans. We shall study 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 will be investigated, and we shall ask if hearing loss can be prevented by attempting to prevent hair cell degeneration.

International collaborations

The team is 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 is 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 collaborates 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

  PUBMED: 19363478; DOI: 10.1038/ng.369; PMC: 2705913

• 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

  PUBMED: 19363479; DOI: 10.1038/ng.355

• 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

  PUBMED: 18996172; DOI: 10.1016/j.neuroscience.2008.10.012

• 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

  PUBMED: 18974863; DOI: 10.1371/journal.pgen.1000238; PMC: 2568954

• 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

  PUBMED: 18833301; DOI: 10.1371/journal.pgen.1000207; PMC: 2543112

• 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

  PUBMED: 18463160; DOI: 10.1093/hmg/ddn140; PMC: 2733815

• 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

  PUBMED: 18160714; DOI: 10.1128/MCB.01282-07; PMC: 2258769

• 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

  PUBMED: 17433286; DOI: 10.1016/j.ydbio.2007.03.011; PMC: 1978180

• 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

  PUBMED: 17326148; DOI: 10.1002/cm.20199; PMC: 2682331

• 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

  PUBMED: 17216607; DOI: 10.1002/dvg.20264; PMC: 2593393

• 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

  PUBMED: 16897347; DOI: 10.1007/s00335-004-2438-5

• 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

  PUBMED: 16627570; DOI: 10.1113/jphysiol.2005.095661; PMC: 1817746

• 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

  PUBMED: 16207732; DOI: 10.1093/hmg/ddi375

• 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

  PUBMED: 15978262; DOI: 10.1016/j.exer.2005.02.014

• 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

  PUBMED: 15846349; DOI: 10.1038/nature03487

Reviews & books

• Genetics.
  Steel KP (2008)
  In: Scott-Brown’s Otorhinolaryngology, Head and Neck Surgery, seventh edition. Hodder/Edward Arnold Publishers, London.
• Genetic and environmental influences on hearing impairment.
  Steel KP (2007)
  In: Genes and Common Diseases - Genetics in Modern Medicine, eds. A F Wright and N D Hastie, Cambridge University Press, Cambridge, pp 505-515.
• Characterising hearing in mice.
  Steel KP (2006)
  In: Standards of Mouse Model Phenotyping, eds M Hrabé de Angelis, P Chambon, SDM Brown. Wiley-VCH, Weinheim. Pp1-14.
• The ear.
  Spiden SL and Steel KP (2006)
  In: Embryos, genes and Birth Defects, eds P Ferretti, A Copp, C Tickle, G Moore. John Wiley, London. Pp231-262.
• Development of the mouse inner ear.
  Kiernan AE, Steel KP and Fekete DM (2002)
  In: Mouse Development, eds J Rossant and PPL Tam. Academic Press, San Diego. Pp539-566.
• Mice as models for human hereditary deafness.
  Steel KP, Erven A and Kiernan AE (2002)
  In: Springer Handbook of Auditory Research, Genetics and Auditory Disorders, eds BJ Keats, AN Popper and RR Fay. Springer, New York. Pp247-296.
• A genetic approach to understanding auditory function.
  Steel KP, Kros CJ
  Nat Genet. 2001;27;143-9. PMID: 11175778 DOI: 10.1038/84758