The neuroepithelia of the inner ear contain hair cells that function as mechanoreceptors to transduce sound and motion signals. Mutations affecting these neuroepithelia cause deafness and vestibular dysfuction in humans1,2,3. Ames waltzer (av) is a recessive mutation found in mice that causes deafness and a balance disorder associated with the degeneration of inner ear neuroepithelia4. Here we report that the gene that harbours the av mutation encodes a novel protocadherin. Cochlear hair cells in the av mutants show abnormal stereocilia by 10 days after birth (P10). This is the first evidence for the requirement of a protocadherin for normal function of the mammalian inner ear.
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Kalatzis, V. & Petit, C. The fundamental and medical impacts of recent progress in research on hereditary hearing loss. Hum. Mol. Genet. 7, 1589–1597 (1998).
Corwin, J.T. Identifying the genes of hearing, deafness, and disequilibrium. Proc. Natl. Acad. Sci. USA 95, 12080– 12082 (1998).
Willems, P.J. Mechanism of disease: genetic causes of hearing loss. N. Engl. J. Med. 342, 1101–1109 ( 2000).
Osako, S. & Hilding, D.A. Electron microscopic studies of capillary permeability in normal and Ames Waltzer deaf mice. Acta Otolaryngol. 71, 365–376 (1971).
Alagramam, K.N. et al. A new mouse insertional mutation that causes sensorineural deafness and vestibular defects. Genetics 152, 1691–1699 (1999).
Alagramam, K.N. et al. Neuroepithelial defects of the inner ear in a new allele of the mouse mutation Ames waltzer. Hear. Res. 148, 181–191 (2000).
Altschul, S.F. et al. Gapped BLAST and PSI-BLAST: a new generation of protein database search programs. Nucleic Acids Res. 25, 3389–3402 (1997).
Uberbacher, E.C. & Mural, R.J. Locating protein-coding regions in human DNA sequences by a multiple sensor-neural network approach . Proc. Natl. Acad. Sci. USA 88, 11261– 11265 (1991).
Xu, Y., Mural, R.J., Shah, M. & Uberbacher, E. Recognizing exons in genomic sequence using GRAIL II. Genet. Eng. (NY) 16, 241–253 (1994).
Suzuki, S.T. Structural and functional diversity of cadherin superfamily: are new members of cadherin superfamily involved in signal transduction pathway? J. Cell. Biochem. 61, 531–542 (1996).
Vanden Heuvel, G.B., Quaggin, S.E. & Igarashi, P. A unique variant of a homeobox gene related to Drosophila cut is expressed in mouse testis. Biol. Reprod. 55, 731–739 (1996).
Schaible, R.H. av. Mouse News Lett. 15, 29 ( 1956).
Schaible, R.H. Ames Waltzer, av. Mouse News Lett. 24, 38 (1961).
Cook, S. & Lane, P. Re-mutation to Ames waltzer. Mouse Genome 91, 554 (1993).
Di Palma, F. et al. Mutations in Cdh23, encoding a new type of cadherin, cause stereocilia disorganization in waltzer, the mouse model for Usher syndrome type 1D. Nature Genet. 27, 103– 107 (2001).
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).
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. (in press).
Perriere, G. & Gouy, M. WWW-query: an on-line retrieval system for biological sequence banks. Biochimie 78, 364– 369 (1996).
Bultman, S.J., Michaud, E.J. & Woychik, R.P. Molecular characterization of the mouse agouti locus . Cell 71, 1195–1204 (1992).
We thank S. Bultman and T. Magnuson for critical reading of the manuscript, and H. Dakappagari for technical assistance. This research was supported by a grant from NIDCD grant 1RO1-DC03420 to R.P.W. and an NRSA fellowship to K.N.A. C.L.M. was supported by NIH training grant HD07104.
Note added in proof: Preliminary data from RNA in situ hybridization on mouse inner ear tissue show expression of Pcdh15 throughout the developing cochlea and in the neuroepithelium and spiral ganglion of the neonate (unpublished data).
Analysis of the predicted protein derived from the candidate gene. a, Amino acid sequence of the protein with the signal sequence underlined once, the transmembrane domain underlined twice and the proline-rich region indicated by a dashed underline. The start of each cadherin repeat (Cr) is designated by an arrow and labeled with repeat number. The end of each repeat is designated by the conserved sequence DXNDNXPXF. The region deleted from Pcdh15av-J is shown in bold italics and that of Pcdh15av-2J in bold. (GIF 46 kb)
Phylogenetic tree comparing cytoplasmic domains of mouse cadherin family members. The tree was constructed using default parameters in the phylup method of the CLUSTAL W program. The tree is unrooted. The scale bar represents one amino acid substitution out of 20 amino acid residues. (GIF 30 kb)
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Alagramam, K., Murcia, C., Kwon, H. et al. The mouse Ames waltzer hearing-loss mutant is caused by mutation of Pcdh15, a novel protocadherin gene. Nat Genet 27, 99–102 (2001). https://doi.org/10.1038/83837
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