Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Mutations in Cdh23, encoding a new type of cadherin, cause stereocilia disorganization in waltzer, the mouse model for Usher syndrome type 1D

Nature Genetics volume 27, pages 103–107 (2001)Cite this article

Abstract

Mouse chromosome 10 harbors several loci associated with hearing loss, including waltzer (v), modifier-of deaf waddler (mdfw) and Age-related hearing loss1 (Ahl). The human region that is orthologous to the mouse 'waltzer' region is located at 10q21–q22 and contains the human deafness loci DFNB12 and USH1D (refs. 2,3). Numerous mutations at the waltzer locus have been documented causing erratic circling and hearing loss4,5,6,7. Here we report the identification of a new gene mutated in v. The 10.5-kb Cdh23 cDNA encodes a very large, single-pass transmembrane protein, that we have called otocadherin. It has an extracellular domain that contains 27 repeats; these show significant homology to the cadherin ectodomain. In v6J, a GT transversion creates a premature stop codon. In vAlb, a CT exchange generates an ectopic donor splice site, effecting deletion of 119 nucleotides of exonic sequence. In v2J, a GA transition abolishes the donor splice site, leading to aberrant splice forms. All three alleles are predicted to cause loss of function. We demonstrate Cdh23 expression in the neurosensory epithelium and show that during early hair-cell differentiation, stereocilia organization is disrupted in v2J homozygotes. Our data indicate that otocadherin is a critical component of hair bundle formation. Mutations in human CDH23 cause Usher syndrome type 1D and thus, establish waltzer as the mouse model for USH1D.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Schematic representation of the mouse otocadherin protein.
Figure 2: Sequence analyses of v mutations.
Figure 3: Expression profile of Cdh23.
Figure 4: SEM analyses of hair cells in v2J mice.
Figure 5: ABR in the C57BL/6J-v2J and B10-v6J strain.

Similar content being viewed by others

Accession codes

Accessions

GenBank/EMBL/DDBJ

References

  1. MGD. Mouse Genome Informatics Project (The Jackson Laboratory, Bar Harbor, Maine, 2000).

  2. Chaib, H. et al. Mapping of DFNB12, a gene for a non-syndromal autosomal recessive deafness, to chromosome 10q21–22. Hum. Mol. Genet. 5, 1061–1064 (1996).

    Article  CAS  Google Scholar 

  3. Wayne, S. et al. Localization of the Usher syndrome type ID gene (Ush1D) to chromosome 10. Hum. Mol. Genet. 5, 1689– 1692 (1996).

    Article  CAS  Google Scholar 

  4. Deol, S.M. A gene for uncomplicated deafness in the mouse. J. Embryol. Exp. Morphol. 4, 190–195 ( 1956).

    Google Scholar 

  5. Deol, M.S. The anatomy and development of the mutants pirouette, shaker-1 and waltzer in the mouse. Proc. Roy. Soc. 145, 206– 213 (1956).

    CAS  Google Scholar 

  6. Bryda, E.C., Ling, H. & Flaherty, L. A high-resolution genetic map around waltzer on mouse chromosome 10 and identification of a new allele of waltzer. Mamm. Genome 8, 1–4 ( 1997).

    Article  CAS  Google Scholar 

  7. Yonezawa, S. et al. Chromosomal localization of a gene responsible for vestibulocochlear defects of BUS/Idr mice: identification as an allele of waltzer. Hear. Res. 134, 116–122 (1999).

    Article  CAS  Google Scholar 

  8. Gumbiner, B.M. Cell adhesion: the molecular basis of tissue architecture and morphogenesis . Cell 84, 345–357 (1996).

    Article  CAS  Google Scholar 

  9. Takeichi, M. Morphogenetic roles of classic cadherins. Curr. Opin. Cell Biol. 7, 619–627 ( 1995).

    Article  CAS  Google Scholar 

  10. Yagi, T. & Takeichi, M. Cadherin superfamily genes: functions, genomic organization, and neurologic diversity. Genes Dev. 14, 1169–1180 (2000).

    CAS  PubMed  Google Scholar 

  11. Yap, A.S., Brieher, W.M. & Gumbiner, B.M. Molecular and functional analysis of cadherin-based adherens junctions. Annu. Rev. Cell Dev. Biol. 13, 119–146 (1997).

    Article  CAS  Google Scholar 

  12. Suzuki, S.T. Protocadherins and diversity of the cadherin superfamily. J. Cell Sci. 109, 2609–2611 ( 1996).

    CAS  PubMed  Google Scholar 

  13. Ozawa, M., Engel, J. & Kemler, R. Single amino acid substitutions in one Ca2+ binding site of uvomorulin abolish the adhesive function. Cell 63, 1033–1038 ( 1990).

    Article  CAS  Google Scholar 

  14. Nollet, F., Kools, P. & van Roy, F. Phylogenetic analysis of the cadherin superfamily allows identification of six major subfamilies besides several solitary members. J. Mol. Biol. 299, 551–572 (2000).

    Article  CAS  Google Scholar 

  15. Noben-Trauth, K., Zheng, Q.Y., Johnson, K.R. & Nishina, P.M. mdfw: a deafness susceptibility locus that interacts with deaf waddler (dfw). Genomics 44, 266– 272 (1997).

    Article  CAS  Google Scholar 

  16. Street, V.A., McKee-Johnson, J.W., Fonseca, R.C., Tempel, B.L. & Noben-Trauth, K. Mutations in a plasma membrane Ca2+-ATPase gene cause deafness in deafwaddler mice. Nature Genet. 19, 390–394 (1998).

    Article  CAS  Google Scholar 

  17. Alagramam, K.N. The mouse Ames waltzer hearing-loss mutant is caused by mutation of Pcdh15 , a new protocadherin gene. Nature Genet. 27, 99–102 (2000).

    Article  Google Scholar 

  18. Yamoah, E.N. et al. Plasma membrane Ca2+-ATPase extrudes Ca2+ from hair cell stereocilia. J. Neurosci. 18, 610–624 (1998).

    Article  CAS  Google Scholar 

  19. Johnson, K.R., Erway, L.C., Cook, S.A., Willott, J.F. & Zheng, Q.Y. A major gene affecting age-related hearing loss in C57BL/6J mice. Hear. Res. 114, 83– 92 (1997).

    Article  CAS  Google Scholar 

  20. Bolz, H. et al. Mutation of CDH23, encoding a new member of the cadherin gene family, causes Usher syndrome type 1D. Nature Genet. 27, 105–112 (2000).

    Google Scholar 

  21. Liu, X., Udovichenko, I.P., Brown, S.D., Steel, K.P. & Williams, D.S. Myosin VIIa participates in opsin transport through the photoreceptor cilium. J. Neurosci. 19, 6267–6274 (1999).

    Article  CAS  Google Scholar 

  22. Schultz, J., Copley, R.R., Doerks, T., Ponting, C.P. & Bork, P. SMART: a web-based tool for the study of genetically mobile domains. Nucleic Acids Res 28, 231 –234 (2000).

    Article  CAS  Google Scholar 

  23. Rost, B. PHD: predicting one-dimensional protein structure by profile-based neural networks. Methods Enzymol. 266, 525– 539 (1996).

    Article  CAS  Google Scholar 

  24. 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).

    Article  CAS  Google Scholar 

  25. Flaherty, L., Messer, A., Russell, L.B. & Rinchik, E.M. Chlorambucil-induced mutations in mice recovered in homozygotes. Proc. Natl. Acad. Sci. USA 89, 2859– 2863 (1992).

    Article  CAS  Google Scholar 

  26. Noben-Trauth, K., Naggert, J.K., North, M.A. & Nishina, P.M. A candidate gene for the mouse mutation tubby. Nature 380, 534–538 (1996).

    Article  CAS  Google Scholar 

  27. Lanford, P.J. et al. Notch signalling pathway mediates hair cell development in mammalian cochlea. Nature Genet. 21, 289 –292 (1999).

    Article  CAS  Google Scholar 

  28. Hunter-Duvar, I.M. A technique for preparation of cochlear specimens for assessment with the scanning electron microscope. Acta Otolaryngol. Suppl. 351, 3–23 (1978).

    Article  CAS  Google Scholar 

  29. Self, T. et al. Shaker-1 mutations reveal roles for myosin VIIA in both development and function of cochlear hair cells. Development 125 , 557–566 (1998).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank M. Legare and W. Frankel for the v6J allele; N. Noben-Trauth for discussions; K. Johnson for access to unpublished data; W. Pavan, D. Drayna and H. Arnheiter for valuable comments on the manuscript; P. Lanford and M. Kelly for help with the in situ hybridization; B. O'Dell for technical assistance; and the staff of our animal facilities. This work was supported by NIH grant DC03771 (E.C.B.), by EC (contract QLG2-CT-1999-00988), MRC and Defeating Deafness (K.P.S.) and the NIDCD Intramural program DZ 00036-04 (K.N.T.).

Author information

Authors and Affiliations

  1. Section on Murine Genetics, Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Rockville, Maryland, USA

    Federica Di Palma, Richard Pellegrino & Konrad Noben-Trauth

  2. Laboratory of Cellular Biology, National Institute on Deafness and Other Communication Disorders, National Institutes of Health , Rockville, Maryland, USA

    Inna A. Belyantseva & Bechara Kachar

  3. MRC Institute of Hearing Research, University Park , Nottingham, UK

    Ralph H. Holme & Karen P. Steel

  4. Department of Microbiology, Immunology & Molecular Genetics, Marshall University School of Medicine, Huntington, West Virginia, USA

    Elizabeth C. Bryda

Authors
  1. Federica Di Palma
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ralph H. Holme
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Elizabeth C. Bryda
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Inna A. Belyantseva
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Richard Pellegrino
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Bechara Kachar
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Karen P. Steel
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Konrad Noben-Trauth
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Konrad Noben-Trauth.

Supplementary information

Figure A

Mouse otocadherin protein; predicted amino acid sequence of mouse otocadherin derived from the C57BL/6J strain. The signal sequence is shown in purple; each ectodomain is highlighted in blue; the predicted transmembrane domain is shown in green and the tyrosine phosphorylation signal is shown in pink. (GIF 239 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Palma, F., Holme, R., Bryda, E. et al. Mutations in Cdh23, encoding a new type of cadherin, cause stereocilia disorganization in waltzer, the mouse model for Usher syndrome type 1D. Nat Genet 27, 103–107 (2001). https://doi.org/10.1038/83660

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/83660

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing