Article

Harmonin Mutations Cause Mechanotransduction Defects in Cochlear Hair Cells

Department of Cell Biology, Institute for Childhood and Neglected Disease, The Scripps Research Institute, La Jolla, CA 92037, USA.
Neuron (Impact Factor: 15.98). 06/2009; 62(3):375-87. DOI: 10.1016/j.neuron.2009.04.006
Source: PubMed

ABSTRACT In hair cells, mechanotransduction channels are gated by tip links, the extracellular filaments that consist of cadherin 23 (CDH23) and protocadherin 15 (PCDH15) and connect the stereocilia of each hair cell. However, which molecules mediate cadherin function at tip links is not known. Here we show that the PDZ-domain protein harmonin is a component of the upper tip-link density (UTLD), where CDH23 inserts into the stereociliary membrane. Harmonin domains that mediate interactions with CDH23 and F-actin control harmonin localization in stereocilia and are necessary for normal hearing. In mice expressing a mutant harmonin protein that prevents UTLD formation, the sensitivity of hair bundles to mechanical stimulation is reduced. We conclude that harmonin is a UTLD component and contributes to establishing the sensitivity of mechanotransduction channels to displacement.

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    • "Mutations in this gene are also responsible for autosomal recessive non-syndromic deafness (Blaydon et al. 2003). USH1C encodes harmonin, which is a scaffolding protein that is required for the normal mechanosensory function of cochlear hair cells (Grillet et al. 2009). This protein might be involved in the maintenance of the synaptic structure or mediating the release of synaptic vesicles in the outer retina (Lillo et al. 2006). "
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    • "This tension is translated either directly or indirectly to MET channels, modulating their open probability. Tip-link tension is modulated by multiple adaptive processes such that MET channel kinetics are at least in part dictated by hair bundle mechanics (Ricci et al. 2005; Vollrath et al. 2007; Wu et al. 1999) and can be modulated by accessory proteins such as harmonin that are found at a distance from the channel (Grillet et al. 2009; Ricci et al. 2006). Thus pore properties such as rectification, ionic permeability, and binding sites within the pore are the most likely candidates to provide direct information about the molecular makeup of the MET channel. "
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    • "Whole-mount staining was carried out as described previously (Grillet et al., 2009b). For scanning electron microscopy (SEM), inner ears were dissected and fixed by local perfusion with 2.5% glutaraldehyde, 4% formaldehyde, 50 mM HEPES buffer (pH 7.2), 2 mM CaCl 2 , 1 mM MgCl 2 and 140 mM NaCl for 2 hours at room temperature. "
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