Compound Heterozygosity of the Functionally Null <i>Cdh23^v-ngt</i> and Hypomorphic <i>Cdh23^ahl</i> Alleles Leads to Early-onset Progressive Hearing Loss in Mice

• Miyasaka Yuki

  Mammalian Genetics Project, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156-8506, Japan Graduate School of Medical and Dental Sciences, Niigata University, 1-757 Asahimachi, Niigata 951-8510, Japan

• Suzuki Sari

  Mammalian Genetics Project, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156-8506, Japan Department of Bioproduction, Tokyo University of Agriculture, 196 Yasaka, Abashiri, Hokkaido 099-2493, Japan

• Ohshiba Yasuhiro

  Mammalian Genetics Project, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156-8506, Japan Graduate School of Medical and Dental Sciences, Niigata University, 1-757 Asahimachi, Niigata 951-8510, Japan

• Watanabe Kei

  Mammalian Genetics Project, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156-8506, Japan Graduate School of Life and Environmental Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8577, Japan

• Sagara Yoshihiko

  Department of Bioproduction, Tokyo University of Agriculture, 196 Yasaka, Abashiri, Hokkaido 099-2493, Japan

• Yasuda Shumpei P.

  Mammalian Genetics Project, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156-8506, Japan

• Matsuoka Kunie

  Mammalian Genetics Project, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156-8506, Japan

• Shitara Hiroshi

  Center for Basic Technology Research, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156-8506, Japan

• Yonekawa Hiromichi

  Center for Basic Technology Research, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156-8506, Japan

• Kominami Ryo

  Graduate School of Medical and Dental Sciences, Niigata University, 1-757 Asahimachi, Niigata 951-8510, Japan

• Kikkawa Yoshiaki

  Mammalian Genetics Project, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156-8506, Japan

Bibliographic Information

Other Title

• Compound Heterozygosity of the Functionally Null Cdh23[v-ngt] and Hypomorphic Cdh23[ahl] Alleles Leads to Early-onset Progressive Hearing Loss in Mice
• Compound heterozygosity of the functionally null <italic>Cdh23</italic>^{<italic>v-ngt</italic>}) and hypomorphic <italic>Cdh23</italic>^{<italic>ahl</italic>} alleles leads to early-onset progressive hearing loss in mice
• Compound heterozygosity of the functionally null <italic>Cdh23^v-ngt</italic> and hypomorphic <italic>Cdh23^ahl</italic> alleles leads to early-onset progressive hearing loss in mice

Abstract

The waltzer (v) mouse mutant harbors a mutation in Cadherin 23 (Cdh23) and is a model for Usher syndrome type 1D, which is characterized by congenital deafness, vestibular dysfunction, and prepubertal onset of progressive retinitis pigmentosa. In mice, functionally null Cdh23 mutations affect stereociliary morphogenesis and the polarity of both cochlear and vestibular hair cells. In contrast, the murine Cdh23^ahl allele, which harbors a hypomorphic mutation, causes an increase in susceptibility to age-related hearing loss in many inbred strains. We produced congenic mice by crossing mice carrying the v niigata (Cdh23^v-ngt) null allele with mice carrying the hypomorphic Cdh23^ahl allele on the C57BL/6J background, and we then analyzed the animals’ balance and hearing phenotypes. Although the Cdh23^v-ngt/ahl compound heterozygous mice exhibited normal vestibular function, their hearing ability was abnormal: the mice exhibited higher thresholds of auditory brainstem response (ABR) and rapid age-dependent elevation of ABR thresholds compared with Cdh23^ahl/ahl homozygous mice. We found that the stereocilia developed normally but were progressively disrupted in Cdh23^v-ngt/ahl mice. In hair cells, CDH23 localizes to the tip links of stereocilia, which are thought to gate the mechanoelectrical transduction channels in hair cells. We hypothesize that the reduction of Cdh23 gene dosage in Cdh23^v-ngt/ahl mice leads to the degeneration of stereocilia, which consequently reduces tip link tension. These findings indicate that CDH23 plays an important role in the maintenance of tip links during the aging process.

Journal

• Experimental Animals

  Experimental Animals 62 (4), 333-346, 2013

  Japanese Association for Laboratory Animal Science

Keywords

• age-related hearing loss
• cadherin 23
• hair cell
• mouse mutant
• stereocilia

Details

• CRID: 1390001205045238528
• NII Article ID: 130003382717
• NII Book ID: AA11032321
• DOI: 10.1538/expanim.62.333
• COI: 1:CAS:528:DC%2BC3sXhslert7nM
• ISSN: 18817122
• ISSN: 00075124
• ISSN: 13411357
• NDL BIB ID: 024933311
• PubMed: 24172198
• Web Site: http://id.ndl.go.jp/bib/024933311
• Web Site: https://ndlsearch.ndl.go.jp/books/R000000004-I024933311
• Web Site: https://www.jstage.jst.go.jp/article/expanim/62/4/62_13-0029/_pdf
• Web Site: https://search.jamas.or.jp/link/ui/2014280873
• Text Lang: en
• Data Source:
  • JaLC
  • NDL
  • Crossref
  • PubMed
  • CiNii Articles
  • KAKEN
• Abstract License Flag: Disallowed