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The mouse Ames waltzer hearing-loss mutant is caused by mutation of Pcdh15, a novel protocadherin gene

Abstract

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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Figure 1: Physical map of the transgene insertion site in Pcdh15av-TgN2742Rpw and summary of cDNA cloning efforts.
Figure 2: Expression of the Pcdh15 in wild-type mice.
Figure 3: Analysis of mutations in the Pcdh15av-J, Pcdh15av-2J and Pcdh15av-3J alleles.
Figure 4: Truncated transcripts in the Pcdh15av-TgN2742Rpw line.
Figure 5: Cochlear neuroepithelium from Pcdh15av-TgN2742Rpw homozygous mutant and a wild-type littermate at P10.

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Acknowledgements

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.

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Correspondence to Richard P. Woychik.

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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expression of Pcdh15 throughout the developing cochlea and in the neuroepithelium and spiral ganglion of the neonate (unpublished data).

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Web Figure A

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)

Web Figure B

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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