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


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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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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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.

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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).

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