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Title
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The CD2 isoform of protocadherin-15 is an essential component of the tip-link complex in mature auditory hair cells
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Author
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Abstract
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| 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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Language
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English
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Source (journal)
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EMBO molecular medicine. - -
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Publication
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2014
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ISSN
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1757-4676
1757-4684
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DOI
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10.15252/EMMM.201403976
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Volume/pages
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6
:7
(2014)
, p. 984-992
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ISI
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000339094500009
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Full text (Publisher's DOI)
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