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: 15.05). 06/2009; 62(3):375-87. DOI: 10.1016/j.neuron.2009.04.006
Source: PubMed


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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Available from: Concepcion Lillo
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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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    • "We used the enhanced method to examine transfection of harmonin in hair cells. In mouse bundles harmonin-EGFP was located near stereocilia tips and was absent from tapers; this localization matched what is seen in acutely dissected mouse cochlea using anti-harmonin antibodies [3]. "
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