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Abstract

Positional cloning of hereditary deafness genes is a direct approach to identify molecules and mechanisms underlying auditory function. Here we report a locus for dominant deafness, DFNA36, which maps to human chromosome 9q13–21 in a region overlapping the DFNB7/B11 locus for recessive deafness. We identified eight mutations in a new gene, transmembrane cochlear-expressed gene 1 (TMC1), in a DFNA36 family and eleven DFNB7/B11 families. We detected a 1.6-kb genomic deletion encompassing exon 14 of Tmc1 in the recessive deafness (dn) mouse mutant, which lacks auditory responses and has hair-cell degeneration1,2. TMC1 and TMC2 on chromosome 20p13 are members of a gene family predicted to encode transmembrane proteins. Tmc1 mRNA is expressed in hair cells of the postnatal mouse cochlea and vestibular end organs and is required for normal function of cochlear hair cells.

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Acknowledgements

We thank the study families for their participation, L. Davis, S.S. Ng, and B. Ploplis for technical assistance; D. Wu, T. Picton, R. Morell, M. Kelley, S. Vreugde and P. Lanford for assistance and advice; C. Morton for providing human fetal cochlear RNA; and P. Steinbach and members of the LMG for helpful discussions. This research was supported by NIDCD/NIH intramural funds from the National Institutes of Health–National Institute on Deafness and Other Communication Disorders (to J.F.B., T.B.F. and A.J.G.).

Author information

Affiliations

  1. Section on Gene Structure and Function, Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, 5 Research Court, Rockville, Maryland 20850, USA.

    • Kiyoto Kurima
    • , Yandan Yang
    • , Tomoko Makishima
    •  & Andrew J. Griffith
  2. Section on Human Genetics, Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, 5 Research Court, Rockville, Maryland 20850, USA.

    • Linda M. Peters
    • , Saima Riazuddin
    • , Zubair M. Ahmed
    • , Sadaf Naz
    • , Jianhong Mo
    • , Edward R. Wilcox
    •  & Thomas B. Friedman
  3. Center of Excellence in Molecular Biology, Punjab University, Thokar Niaz Baig, Lahore, Pakistan.

    • Zubair M. Ahmed
    • , Shaheen Khan
    •  & Sheikh Riazuddin
  4. Department of Genetics, Louisiana State University Health Sciences Center, New Orleans, Louisiana, USA.

    • Deidre Arnaud
    • , Stacy Drury
    •  & Bronya J.B. Keats
  5. Genetics Unit, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India.

    • Manju Ghosh
    •  & P.S.N. Menon
  6. Rotary Deaf School, Ichalkaranji-Tilawani, Maharashtra, India.

    • Dilip Deshmukh
  7. Human Genetics Program, Department of Pediatrics, New York University School of Medicine, New York, New York, USA.

    • Carole Oddoux
    •  & Harry Ostrer
  8. Department of Environmental Health Sciences, Tulane University Medical Center, New Orleans, Louisiana, USA.

    • Prescott L. Deininger
  9. G-protein Coupled Receptors' Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, 50 Center Drive, Bethesda, Maryland, USA.

    • Lori L. Hampton
    •  & James F. Battey Jr.
  10. Section on Molecular Neuroscience, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, 5 Research Court, Rockville, Maryland 20850, USA.

    • Susan L. Sullivan
  11. Hearing Section, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, 5 Research Court, Rockville, Maryland 20850, USA.

    • Andrew J. Griffith

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Competing interests

A.J.G., K.K., T.B.F. and E.R.W. have filed a patent application for the genes TMC1, Tmc1, TMC2 and Tmc2.

Corresponding author

Correspondence to Andrew J. Griffith.

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DOI

https://doi.org/10.1038/ng842