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Dominant and recessive deafness caused by mutations of a novel gene, TMC1, required for cochlear hair-cell function

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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Figure 1: DFNA36 and DFNB7/B11 families.
Figure 2: Physical map of the DFNA36/B7/B11 region defined by critical recombinations in families LMG128, PKSR9 and PKSR25.
Figure 3: Clustal W alignment of deduced amino-acid sequences of TMC1, Tmc1, TMC2 and Tmc2 (ref. 17).
Figure 4: TMC1 mutations segregating in DFNA36 and DFNB7/B11 families.
Figure 5: Intragenic deletion of exon 14 of Tmc1 in deafness (dn) mice.
Figure 6: Tmc1 mRNA expression in mouse inner ear.

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References

  1. 1

    Steel, K.P. & Bock, G.R. The nature of inherited deafness in deafness mice. Nature 288, 159–161 (1980).

    CAS  Article  Google Scholar 

  2. 2

    Bock, G.R. & Steel, K.P. Inner ear pathology in the deafness mutant mouse. Acta Otolaryngol. 96, 39–47 (1983).

    CAS  Article  Google Scholar 

  3. 3

    Ashmore, J.F. & Mammano, F. Can you still see the cochlea for the molecules? Curr. Opin. Neurobiol. 11, 449–454 (2001).

    CAS  Article  Google Scholar 

  4. 4

    Griffith, A.J. & Friedman, T.B. Making sense out of sound. Nature Genet. 21, 347–349 (1999).

    CAS  Article  Google Scholar 

  5. 5

    Gillespie, P.G. & Walker, R.G. Molecular basis of mechanosensory transduction. Nature 413, 194–202 (2001).

    CAS  Article  Google Scholar 

  6. 6

    Ahmed, Z.M. et al. Mutations of the protocadherin gene PCDH15 cause Usher syndrome type 1F. Am. J. Hum. Genet. 69, 25–34 (2001).

    CAS  Article  Google Scholar 

  7. 7

    Alagramam, K.N. et al. The mouse Ames waltzer hearing-loss mutant is caused by mutation of Pcdh15, a novel protocadherin gene. Nature Genet. 27, 99–102 (2001).

    CAS  Article  Google Scholar 

  8. 8

    Bolz, H. et al. Mutation of CDH23, encoding a new member of the cadherin gene family, causes Usher syndrome type 1D. Nature Genet. 27, 108–112 (2001).

    CAS  Article  Google Scholar 

  9. 9

    Bork, J.M. et al. Usher syndrome 1D and nonsyndromic autosomal recessive deafness DFNB12 are caused by allelic mutations of the novel cadherin-like gene CDH23. Am. J. Hum. Genet. 68, 26–37 (2001).

    CAS  Article  Google Scholar 

  10. 10

    Verpy, E. et al. Mutations in a new gene encoding a protein of the hair bundle cause non-syndromic deafness at the DFNB16 locus. Nature Genet. 29, 345–349 (2001).

    CAS  Article  Google Scholar 

  11. 11

    Wilcox, E.R. et al. Mutations in the gene encoding tight junction claudin-14 cause autosomal recessive deafness DFNB29. Cell 104, 165–172 (2001).

    CAS  Article  Google Scholar 

  12. 12

    Jain, P.K. et al. A human recessive neurosensory nonsyndromic hearing impairment locus is potential homologue of murine deafness (dn) locus. Hum. Mol. Genet. 4, 2391–2394 (1995).

    CAS  Article  Google Scholar 

  13. 13

    Scott, D.A. et al. An autosomal recessive nonsyndromic-hearing-loss locus identified by DNA pooling using two inbred Bedouin kindreds. Am. J. Hum. Genet. 59, 385–391 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 14

    Scott, D.A. et al. Refining the DFNB7-DFNB11 deafness locus using intragenic polymorphisms in a novel gene, TMEM2. Gene 246, 265–274 (2000).

    CAS  Article  Google Scholar 

  15. 15

    Suzuki, Y. et al. Statistical analysis of the 5′ untranslated region of human mRNA using “Oligo-Capped” cDNA libraries. Genomics 64, 286–297 (2000).

    CAS  Article  Google Scholar 

  16. 16

    Kozak, M. Compilation and analysis of sequences upstream from the translational start site in eukaryotic mRNAs. Nucleic Acids Res. 12, 857–872 (1984).

    CAS  Article  Google Scholar 

  17. 17

    Thompson, J.D., Higgins, D.G. & Gibson, T.J. CLUSTAL W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice. Nucleic Acids Res. 22, 4673–4680 (1994).

    CAS  Article  Google Scholar 

  18. 18

    Keats, B.J. et al. The deafness locus (dn) maps to mouse chromosome 19. Mamm. Genome 6, 8–10 (1995).

    CAS  Article  Google Scholar 

  19. 19

    Moller, S., Croning, M.D. & Apweiler, R. Evaluation of methods for the prediction of membrane spanning regions. Bioinformatics 17, 646–653 (2001).

    CAS  Article  Google Scholar 

  20. 20

    Nielsen, H., Engelbrecht, J., Brunak, S. & von Heijne, G. Identification of prokaryotic and eukaryotic signal peptides and prediction of their cleavage sites. Protein Eng. 10, 1–6 (1997).

    CAS  Article  Google Scholar 

  21. 21

    Wang, A. et al. Association of unconventional myosin MYO15 mutations with human nonsyndromic deafness DFNB3. Science 280, 1447–1451 (1998).

    CAS  Article  Google Scholar 

  22. 22

    Liang, Y. et al. Characterization of the human and mouse unconventional myosin XV genes responsible for hereditary deafness DFNB3 and shaker 2. Genomics 61, 243–258 (1999).

    CAS  Article  Google Scholar 

  23. 23

    Belyantseva, I.A., Adler, H.J., Curi, R., Frolenkov, G.I. & Kachar, B. Expression and localization of prestin and the sugar transporter GLUT-5 during development of electromotility in cochlear outer hair cells. J. Neurosci. 20, RC116 (2000).

    CAS  Article  Google Scholar 

  24. 24

    Vinas, A.M. et al. The mouse deafness locus (dn) is associated with an inversion on chromosome 19. Biochim. Biophys. Acta 1407, 257–262 (1998).

    CAS  Article  Google Scholar 

  25. 25

    Vreugde, S. et al. Beethoven, a mouse model for dominant progressive hearing loss DFNA36. Nature Genet., 30, 257–258 (2002).

    Article  Google Scholar 

  26. 26

    Clapham, D.E., Runnels, L.W. & Strübing, C. The TRP ion channel family. Nature Rev. Neurosci. 2, 387–396 (2001).

    CAS  Article  Google Scholar 

  27. 27

    Huang, J.M., Berlin, C.I., Lin, S.T. & Keats, B.J. Low intensities and 1.3 ratio produce distortion product otoacoustic emissions which are larger in heterozygous (+/dn) than homozygous (+/+) mice. Hear. Res. 117, 24–30 (1998).

    CAS  Article  Google Scholar 

  28. 28

    Deol, M.S. & Kocher, W. A new gene for deafness in the mouse. Heredity 12, 463–466 (1958).

    Article  Google Scholar 

  29. 29

    Kiernan, A.E. et al. Tailchaser (Tlc): a new mouse mutation affecting hair bundle differentiation and hair cell survival. J. Neurocytol. 28, 969–985 (1999).

    CAS  Article  Google Scholar 

  30. 30

    Romero, P. et al. Sequence complexity of disordered protein. Proteins 42, 38–48 (2001).

    CAS  Article  Google Scholar 

  31. 31

    Pujol, R., Shnerson, A., Lenoir, M. & Deol, M.S. Early degeneration of sensory and ganglion cells in the inner ear of mice with uncomplicated genetic deafness (dn): preliminary observations. Hear. Res. 12, 57–63 (1983).

    CAS  Article  Google Scholar 

  32. 32

    Hudspeth, A.J. & Corey, D.P. Sensitivity, polarity, and conductance change in the response of vertebrate hair cells to controlled mechanical stimuli. Proc. Natl Acad. Sci. U S A 74, 2407–2411 (1977).

    CAS  Article  Google Scholar 

  33. 33

    Rivolta, M.N. et al. Auditory hair cell precursors immortalized from the mammalian inner ear. Proc. R. Soc. Lond. B Biol. Sci. 265, 1595–1603 (1998).

    CAS  Article  Google Scholar 

  34. 34

    Venter, J.C. et al. The sequence of the human genome. Science 291, 1304–1351 (2001).

    CAS  Article  Google Scholar 

  35. 35

    Ressler, K.J., Sullivan, S.L. & Buck, L.B. Information coding in the olfactory system: evidence for a stereotyped and highly organized epitope map in the olfactory bulb. Cell 79, 1245–1255 (1994).

    CAS  Article  Google Scholar 

  36. 36

    Sassoon, D.A., Garner, I. & Buckingham, M. Transcripts of alpha-cardiac and alpha-skeletal actins are early markers for myogenesis in the mouse embryo. Development 104, 155–164 (1988).

    CAS  PubMed  PubMed Central  Google Scholar 

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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.).

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Correspondence to Andrew J. Griffith.

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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.

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Kurima, K., Peters, L., Yang, Y. et al. Dominant and recessive deafness caused by mutations of a novel gene, TMC1, required for cochlear hair-cell function. Nat Genet 30, 277–284 (2002). https://doi.org/10.1038/ng842

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