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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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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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