The CD2 isoform of protocadherin-15 is an essential component of the tip-link complex in mature auditory hair cells

EMBO Mol Med. 2014 Jul;6(7):984-92. doi: 10.15252/emmm.201403976.


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 (Pcdh15ex38-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.

Keywords: auditory mechano‐electrical transduction; deafness; protocadherin‐15; stereocilia; tip‐link.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cadherin Related Proteins
  • Cadherins / analysis
  • Cadherins / genetics*
  • Child
  • Deafness / genetics*
  • Female
  • Frameshift Mutation
  • Hair Cells, Auditory / cytology*
  • Hair Cells, Auditory / metabolism
  • Hair Cells, Auditory / ultrastructure
  • Humans
  • Male
  • Mechanotransduction, Cellular
  • Mice
  • Mice, Knockout
  • Mutation
  • Protein Isoforms / analysis
  • Protein Isoforms / genetics
  • Protein Precursors / analysis
  • Protein Precursors / genetics*


  • CDHR15 protein, mouse
  • CDHR15, human
  • Cadherin Related Proteins
  • Cadherins
  • Protein Isoforms
  • Protein Precursors