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| Subject Categories: Neuroscience |
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| The EMBO Journal
(2006) 25, 642–652, doi:10.1038/sj.emboj.7600951 Published online 26 January 2006 |
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| Mice with altered KCNQ4 K+ channels implicate sensory outer hair cells in human progressive deafness |
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| Tatjana Kharkovets1, Karin Dedek1, 4, Hannes Maier2, Michaela Schweizer1, Darina Khimich3, Régis Nouvian3, Vitya Vardanyan1, Rudolf Leuwer2, Tobias Moser3 and Thomas J Jentsch1 |
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1 Zentrum für Molekulare Neurobiologie, ZMNH, Universität Hamburg, Hamburg, Germany 2 Department of Otolaryngology, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany 3 Department of Otolaryngology, Center for Molecular Physiology of the Brain, University of Göttingen, Göttingen, Germany To whom correspondence should be addressed Thomas J Jentsch, Zentrum für Molekulare Neurobiologie, ZMNH, Universität Hamburg, Falkenried 94, Hamburg 20246, Germany. Tel.: +49 40 42803 4741; Fax: +49 40 42803 4839; E-mail: Jentsch@zmnh.uni-hamburg.de 4 Present address: Carl-von-Ossietzky-Universität Oldenburg, Carl-von-Ossietzky-Strasse 9-11, 26111 Oldenburg, Germany Received 29 July 2005; Accepted 19 December 2005; Published online 26 January 2006. |
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| Abstract |
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| KCNQ4 is an M-type K+ channel expressed in sensory hair cells of the inner ear and in the central auditory pathway. KCNQ4 mutations underlie human DFNA2 dominant progressive hearing loss. We now generated mice in which the KCNQ4 gene was disrupted or carried a dominant negative DFNA2 mutation. Although KCNQ4 is strongly expressed in vestibular hair cells, vestibular function appeared normal. Auditory function was only slightly impaired initially. It then declined over several weeks in Kcnq4-/- mice and over several months in mice carrying the dominant negative allele. This progressive hearing loss was paralleled by a selective degeneration of outer hair cells (OHCs). KCNQ4 disruption abolished the IK,n current of OHCs. The ensuing depolarization of OHCs impaired sound amplification. Inner hair cells and their afferent synapses remained mostly intact. These cells were only slightly depolarized and showed near-normal presynaptic function. We conclude that the hearing loss in DFNA2 is predominantly caused by a slow degeneration of OHCs resulting from chronic depolarization. |
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| Keywords: capacitance, channelopathy, KCNQ5, ribbon synapse, vestibular organ |
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