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A Myo7a mutation cosegregates with stereocilia defects and low-frequency hearing impairment

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Abstract

A phenotype-driven approach was adopted in the mouse to identify molecules involved in ear development and function. Mutant mice were obtained using N-ethyl-N-nitrosourea (ENU) mutagenesis and were screened for dominant mutations that affect hearing and/or balance. Heterozygote headbanger (Hdb/+) mutants display classic behavior indicative of vestibular dysfunction including hyperactivity and head bobbing, and they show a Preyer reflex in response to sound but have raised cochlear thresholds especially at low frequencies. Scanning electron microscopy of the surface of the organ of Corti revealed abnormal stereocilia bundle development from an early age that was more severe in the apex than the base. Utricular stereocilia were long, thin, and wispy. Homozygotes showed a similar but more severe phenotype. The headbanger mutation has been mapped to a 1.5-cM region on mouse Chromosome 7 in the region of the unconventional myosin gene Myo7a, and mutation screening revealed an A>T transversion that is predicted to cause an isoleucine-to-phenylalanine amino acid substitution (I178F) in a conserved region in the motor-encoding domain of the gene. Protein analysis revealed reduced levels of myosin VIIa expression in inner ears of headbanger mice. Headbanger represents a novel inner ear phenotype and provides a potential model for low-frequency-type human hearing loss.

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References

  • AM Ahmed S Riazuddin SL Bernstein Ahmed Z Khan S et al. (2001) ArticleTitleMutations of the protocadherin gene PCDH15 cause Usher syndrome type 1F Am J Hum Genet 69 25–34 Occurrence Handle10.1086/321277 Occurrence Handle1:CAS:528:DC%2BD3MXls1emtrg%3D Occurrence Handle11398101

    Article  CAS  PubMed  Google Scholar 

  • KN Alagramam CL Murcia HY Kwon Pawlowski KS CG Wright RP Woychik et al. (2001) ArticleTitle The mouse Ames Waltzer hearing-loss mutant is caused by mutation of Pcdh15, a novel protocadherin gene Nat Genet 27 99–102 Occurrence Handle1:CAS:528:DC%2BD3MXis1yrsQ%3D%3D Occurrence Handle11138007

    CAS  PubMed  Google Scholar 

  • LM Astuto PM Kelley JW Askew MD Weston RJ Smith et al. (2002) ArticleTitleSearching for evidence of DFNB2 Am J Med Genet 109 291–297 Occurrence Handle10.1002/ajmg.10384 Occurrence Handle11992483

    Article  PubMed  Google Scholar 

  • H Bolz B Brederlow Particlevon A Ramirez EC Bryda K Kutsche et al. (2001) ArticleTitleMutation of CDH23, endocding a new member of the cadherin gene family, cause Usher syndrome type 1D Nat Genet 27 108–112 Occurrence Handle10.1038/83667 Occurrence Handle1:CAS:528:DC%2BD3MXis1yrtw%3D%3D Occurrence Handle11138009

    Article  CAS  PubMed  Google Scholar 

  • JA Curtin E Quint V Tsipouri RM Arkell B Cattanach et al. (2003) ArticleTitleMutation of Celsr1 disrupts planar polarity of inner ear hair cells and causes severe neural tube defects in the mouse Curr Biol 13 1129–1133 Occurrence Handle10.1016/S0960-9822(03)00374-9 Occurrence Handle1:CAS:528:DC%2BD3sXlt1ent74%3D Occurrence Handle12842012

    Article  CAS  PubMed  Google Scholar 

  • F Di Palma RH Holme EC Bryda IA Belyantseva R Pellegrino et al. (2001) ArticleTitle Mutations in Cdh23, encoding a new type of cadherin, cause stereocilia disorganization in waltzer, the mouse model for Usher syndrome type 1D Nat Genet 27 103–107 Occurrence Handle10.1038/83660 Occurrence Handle1:CAS:528:DC%2BD3MXis1yrtg%3D%3D Occurrence Handle11138008

    Article  CAS  PubMed  Google Scholar 

  • F Donaudy A Ferrara L Esposito R Hertzano O Ben-David et al. (2003) ArticleTitleMultiple mutations of MYO1A, a cochlear-expressed gene, in sensorineural hearing loss Am J Hum Genet 72 1571–1577 Occurrence Handle10.1086/375654 Occurrence Handle1:CAS:528:DC%2BD3sXktlyitLY%3D Occurrence Handle12736868

    Article  CAS  PubMed  Google Scholar 

  • G Ehret (1975) ArticleTitleMasked auditory thresholds, critical ratios, and scales of the basilar membrane of the housemouse (Mus musculus) J Comp Physiol 103 329–341

    Google Scholar 

  • A Erven MJ Skynner K Okumura S Takebayashi SD Brown et al. (2002) ArticleTitleA novel stereocilia defect in sensory hair cells of the deaf mouse mutant Tasmanian devil Eur J Neurosci 16 1433–1441 Occurrence Handle10.1046/j.1460-9568.2002.02213.x Occurrence Handle12405956

    Article  PubMed  Google Scholar 

  • F Gibson J Walsh P Mburu A Varela KA Brown et al. (1995) ArticleTitleA type VII myosin encoded by the mouse deafness gene shaker-1 Nature 374 62–64 Occurrence Handle10.1038/374062a0 Occurrence Handle1:CAS:528:DyaK2MXktFCrt74%3D Occurrence Handle7870172

    Article  CAS  PubMed  Google Scholar 

  • F Glaser T Pupko I Paz RE Bell D Bechor–Shental et al. (2003) ArticleTitleConSurf: identification of functional regions in proteins by surface-mapping of phylogenetic information Bioinformatics 19 163–164 Occurrence Handle10.1093/bioinformatics/19.1.163 Occurrence Handle1:CAS:528:DC%2BD3sXltF2rtQ%3D%3D Occurrence Handle12499312

    Article  CAS  PubMed  Google Scholar 

  • T Hasson MB Heintzelman J Santos–Sacchi DP Corey MS Mooseker (1995) ArticleTitleExpression in cochlea and retina of myosin VIIa, the gene product defective in Usher syndrome type 1B Proc Natl Acad Sci USA 92 9815–9819 Occurrence Handle1:CAS:528:DyaK2MXoslCmtrg%3D Occurrence Handle7568224

    CAS  PubMed  Google Scholar 

  • T Hasson J Walsh J Cable MS Mooseker SD Brown et al. (1997) ArticleTitleEffects of shaker-1 mutations on myosin-VIIa protein and mRNA expression Cell Motil Cytoskeleton 37 127–138 Occurrence Handle1:CAS:528:DyaK2sXktVyqtLg%3D Occurrence Handle9186010

    CAS  PubMed  Google Scholar 

  • RH Holme KP Steel (2002) ArticleTitleStereocilia defects in waltzer (Cdh23) shaker1 (Myo7a) and double waltzer/shaker1 mutant mice Hear Res 169 13–23 Occurrence Handle10.1016/S0378-5955(02)00334-9 Occurrence Handle1:CAS:528:DC%2BD38Xlt12mtL8%3D Occurrence Handle12121736

    Article  CAS  PubMed  Google Scholar 

  • MH HrabéAngelis Particlede H Flaswinkel H Fuchs B Rathkolb D Soewarto et al. (2000) ArticleTitleGenome-wide, large-scale production of mutant mice by ENU mutagenesis Nat Genet 25 444–447 Occurrence Handle10.1038/78146 Occurrence Handle1:STN:280:DC%2BD3cvgvFGhug%3D%3D Occurrence Handle10932192

    Article  CAS  PubMed  Google Scholar 

  • JA Kaltenbach PR Falzarano TH Simpson (1994) ArticleTitlePostnatal development of the hamster cochlea, II. Growth and differentiation of Stereocilia bundles J Comp Neurol 350 187–198 Occurrence Handle1:STN:280:ByqC1M%2FgvFA%3D Occurrence Handle7884037

    CAS  PubMed  Google Scholar 

  • MW Kelley XM Xu MA Wagner ME Warchol JT Corwin (1993) ArticleTitleThe developing organ of Corti contains retinoic acid and forms supernumerary hair cells in response to exogenous retinoic acid in culture Development 119 1041–1053 Occurrence Handle1:CAS:528:DyaK2cXitFemsLs%3D Occurrence Handle8306874

    CAS  PubMed  Google Scholar 

  • AE Kiernan M Zalzman H Fuchs MH Angelis Particlede R Balling et al. (1999) ArticleTitleTailchaser (Tlc): a new mouse mutation affecting hair bundle differentiation and hair cell survival J Neurocytol 28 969–985 Occurrence Handle10.1023/A:1007090626294 Occurrence Handle1:CAS:528:DC%2BD3cXmsFalu7s%3D Occurrence Handle10900098

    Article  CAS  PubMed  Google Scholar 

  • M Kollmar U Durrwang W Kliche DJ Manstein FJ Kull (2002) ArticleTitleCrystal structure of the motor domain of a class-I myosin EMBO J 21 2517–2525 Occurrence Handle10.1093/emboj/21.11.2517 Occurrence Handle1:CAS:528:DC%2BD38XkvV2ju7Y%3D Occurrence Handle12032065

    Article  CAS  PubMed  Google Scholar 

  • G Levy F Levi–Acobas S Blanchard S Gerber D Larget–Piet et al. (1997) ArticleTitleMyosin VIIA gene: heterogeneity of the mutations responsible for Usher syndrome type IB Hum Mol Genet 6 111–116 Occurrence Handle10.1093/hmg/6.1.111 Occurrence Handle1:CAS:528:DyaK2sXlslClsA%3D%3D Occurrence Handle9002678

    Article  CAS  PubMed  Google Scholar 

  • RT Libby KP Steel (2001) ArticleTitleElectroretinographic anomalies in mice with mutations in Myo7a, the gene involved in human Usher syndrome type 1B Invest Ophthalmol Vis Sci 42 770–778 Occurrence Handle1:STN:280:DC%2BD3M7lt1Citg%3D%3D Occurrence Handle11222540

    CAS  PubMed  Google Scholar 

  • XZ Liu VE Newton KP Steel SD Brown (1997a) ArticleTitleIdentification of a new mutation of the myosin VII head region in Usher syndrome type 1 Hum Mutat 10 168–170 Occurrence Handle1:CAS:528:DyaK2sXls1Srtr8%3D

    CAS  Google Scholar 

  • XZ Liu J Walsh Y Tamagawa K Kitamura M Nishizawa et al. (1997b) ArticleTitleAutosomal dominant non-syndromic deafness caused by a mutation in the myosin VIIA gene Nat Genet 17 268–269 Occurrence Handle1:CAS:528:DyaK2sXntVShtLg%3D

    CAS  Google Scholar 

  • P Martin GJ Swanson (1993) ArticleTitleDescriptive and experimental analysis of the epithelial remodellings that control semicircular canal formation in the developing mouse inner ear Dev Biol 159 549–558 Occurrence Handle10.1006/dbio.1993.1263 Occurrence Handle1:STN:280:ByuD3cbptlU%3D Occurrence Handle8405678

    Article  CAS  PubMed  Google Scholar 

  • FJ Probst RA Fridell Y Raphael TL Saunders A Wang et al. (1998) ArticleTitleCorrection of deafness in shaker-2 mice by an unconventional myosin in a BAC transgene Science 280 1444–1447 Occurrence Handle10.1126/science.280.5368.1444 Occurrence Handle1:CAS:528:DyaK1cXjtlaku7Y%3D Occurrence Handle9603735

    Article  CAS  PubMed  Google Scholar 

  • T Self M Mahony J Fleming J Walsh SD Brown et al. (1998) ArticleTitleShaker-1 mutations reveal roles for myosin VIIA in both development and function of cochlear hair cells Development 125 557–566 Occurrence Handle1:CAS:528:DyaK1cXhvFWhu7o%3D Occurrence Handle9435277

    CAS  PubMed  Google Scholar 

  • T Self T Sobe NG Copeland NA Jenkins KB Avraham et al. (1999) ArticleTitleRole of myosin VI in the differentiation of cochlear hair cells Dev Biol 214 331–341 Occurrence Handle10.1006/dbio.1999.9424 Occurrence Handle1:CAS:528:DyaK1MXms1CrtL8%3D Occurrence Handle10525338

    Article  CAS  PubMed  Google Scholar 

  • KP Steel RJ Smith (1992) ArticleTitleNormal hearing in Splotch (Sp/+), the mouse homologue of Waardenburg syndrome type 1 Nat Genet 2 75–79 Occurrence Handle10.1038/ng0992-75 Occurrence Handle1:STN:280:ByyB28rht1w%3D Occurrence Handle1303254

    Article  CAS  PubMed  Google Scholar 

  • VA Street JC Kallman KL Kiemele (2004) ArticleTitleModifier controls severity of a novel dominant low frequency myosin VIIA (MYO7A) auditory mutation J Med Genet 41 e62 Occurrence Handle10.1136/jmg.2003.013557 Occurrence Handle1:STN:280:DC%2BD2c3itlWrsA%3D%3D Occurrence Handle15121790

    Article  CAS  PubMed  Google Scholar 

  • Y Tamagawa K Ishikawa T Ishida K Kitamura S Makino et al. (2002) ArticleTitlePhenotype of DFNA11: a nonsyndromic hearing loss caused by a myosin VIIA mutation Laryngoscope 112 292–297 Occurrence Handle10.1097/00005537-200202000-00017 Occurrence Handle1:CAS:528:DC%2BD38XnvVegsb8%3D Occurrence Handle11889386

    Article  CAS  PubMed  Google Scholar 

  • LG Tilney MS Tilney DJ DeRosier (1992) ArticleTitleActin filaments, stereocilia, and hair cells: how cells count and measure Annu Rev Cell Biol 8 257–274 Occurrence Handle1:STN:280:ByyC3Mbntlw%3D Occurrence Handle1476800

    CAS  PubMed  Google Scholar 

  • S Vreugde A Erven CJ Kros W Marcotti H Fuchs et al. (2002) ArticleTitleBeethoven, a mouse model for dominant, progressive hearing loss DFNA36 Nat Genet 30 257–258 Occurrence Handle10.1038/ng848 Occurrence Handle11850623

    Article  PubMed  Google Scholar 

  • D Weil S Blanchard J Kaplan P Guilford F Gibson et al. (1995) ArticleTitleDefective myosin VIIA gene responsible for Usher syndrome type 1B Nature 374 60–61 Occurrence Handle10.1038/374060a0 Occurrence Handle1:STN:280:ByqC2svovVQ%3D Occurrence Handle7870171

    Article  CAS  PubMed  Google Scholar 

  • D Weil G Levy I Sahly F Levi–Acobas S Blanchard et al. (1996) ArticleTitleHuman myosin VIIA responsible for the Usher 1B syndrome: a predicted membrane-associated motor protein expressed in developing sensory epithelia Proc Natl Acad Sci USA 93 3232–3237 Occurrence Handle10.1073/pnas.93.8.3232 Occurrence Handle1:CAS:528:DyaK28XisVWis74%3D Occurrence Handle8622919

    Article  CAS  PubMed  Google Scholar 

  • D Weil P Kussel S Blanchard G Levy F Levi–Acobas et al. (1997) ArticleTitleThe autosomal recessive isolated deafness, DFNB2, and the Usher 1B syndrome are allelic defects of the myosin-VIIA gene Nat Genet 16 191–193 Occurrence Handle10.1038/ng0697-191 Occurrence Handle1:CAS:528:DyaK2sXjs1eitLg%3D Occurrence Handle9171833

    Article  CAS  PubMed  Google Scholar 

  • MD Weston PM Kelley LD Overbeck M Wagenaar DJ Orten et al. (1996) ArticleTitleMyosin VIIA mutation screening in 189 Usher syndrome type 1 patients Am J Hum Genet 59 1074–1083 Occurrence Handle1:CAS:528:DyaK28XmvFyks7o%3D Occurrence Handle8900236

    CAS  PubMed  Google Scholar 

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Acknowledgments

We thank Ralph Holme and Rick Libby for help with the complementation test, Nadav Ahituv for help with phenotyping, and Tama Hasson for myosin antibodies. This work was supported by the MRC, Defeating Deafness, the European Commission (QLRT-CT-1999-00988), the German Human Genome Project (DHGP), the German National Genome Network (NGFN), the German–Israeli Foundation for Scientific Research and Development (GIF), and the Israel Ministry of Health. This work was performed in the partial fulfillment of the requirements for an M.D.–Ph.D. degree of Ronna Hertzano, Faculty of Medicine, Tel Aviv University, Israel, and the Ph.D. degree of Charlotte Rhodes, University of Nottingham, UK.

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Authors and Affiliations

  1. MRC Institute of Hearing Research, University Park, Nottingham, NG7 2RD, UK

    Charlotte R. Rhodes & Karen P. Steel

  2. Department of Human Genetics and Molecular Medicine, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel

    Ronna Hertzano, Rachel E. Bell & Karen B. Avraham

  3. GSF Research Center for Environment and Health, Institute of Experimental Genetics, Neuherberg, Germany

    Helmut Fuchs & Martin Hrabé de Angelis

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

    Karen P. Steel

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  1. Charlotte R. Rhodes
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  2. Ronna Hertzano
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  3. Helmut Fuchs
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  4. Rachel E. Bell
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  5. Martin Hrabé de Angelis
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  6. Karen P. Steel
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  7. Karen B. Avraham
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Correspondence to Karen P. Steel.

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These authors contributed equally to this study.

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Rhodes, C.R., Hertzano, R., Fuchs, H. et al. A Myo7a mutation cosegregates with stereocilia defects and low-frequency hearing impairment. Mamm Genome 15, 686–697 (2004). https://doi.org/10.1007/s00335-004-2344-x

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  • DOI: https://doi.org/10.1007/s00335-004-2344-x

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