期刊
EMBO MOLECULAR MEDICINE
卷 6, 期 7, 页码 984-992出版社
WILEY-BLACKWELL
DOI: 10.15252/emmm.201403976
关键词
auditory mechano-electrical transduction; deafness; protocadherin-15; stereocilia; tip-link
资金
- Fondation Raymonde et Guy Strittmatter
- ERC-Hair bundle [ERC-2011-ADG_294570]
- Foundation BNP Paribas
- LHW-Stiftung
- Tassili project
- Wellcome Trust [WT087377]
- French state funds [ANR-10-LABX-65]
- ANR within the Investissements d'Avenir programme [ANR-11-IDEX-0004-02]
Protocadherin-15 (Pcdh15) is a component of the tip-links, the extracellular filaments that gate hair cell mechano-electrical transduction channels in the inner ear. There are three Pcdh15 splice isoforms (CD1, CD2 and CD3), which only differ by their cytoplasmic domains; they are thought to function redundantly in mechano-electrical transduction during hair-bundle development, but whether any of these isoforms composes the tip-link in mature hair cells remains unknown. By immunolabelling and both morphological and electrophysiological analyses of post-natal hair cell-specific conditional knockout mice (Pcdh15(ex38-fl/ex38-fl) Myo15-cre(+/-)) that lose only this isoform after normal hair-bundle development, we show that Pcdh15-CD2 is an essential component of tip-links in mature auditory hair cells. The finding, in the homozygous or compound heterozygous state, of a PCDH15 frameshift mutation (p. P1515Tfs*4) that affects only Pcdh15-CD2, in profoundly deaf children from two unrelated families, extends this conclusion to humans. These results provide key information for identification of new components of the mature auditory mechano-electrical transduction machinery. This will also serve as a basis for the development of gene therapy for deafness caused by PCDH15 defects.
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