title: Mice with altered KCNQ4 K+ channels implicate sensory outer hair cells in human progressive deafness.
abstract: 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 I(K,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.
authors.affiliation: Zentrum für Molekulare Neurobiologie, ZMNH, Universität Hamburg, Hamburg, Germany.
authors.forename: Tatjana
authors.initials: T
authors.lastname: Kharkovets
authors.forename: Karin
authors.initials: K
authors.lastname: Dedek
authors.forename: Hannes
authors.initials: H
authors.lastname: Maier
authors.forename: Michaela
authors.initials: M
authors.lastname: Schweizer
authors.forename: Darina
authors.initials: D
authors.lastname: Khimich
authors.forename: Régis
authors.initials: R
authors.lastname: Nouvian
authors.forename: Vitya
authors.initials: V
authors.lastname: Vardanyan
authors.forename: Rudolf
authors.initials: R
authors.lastname: Leuwer
authors.forename: Tobias
authors.initials: T
authors.lastname: Moser
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Jentsch
mesh_terms: D000818:Animals; D016764:Cell Polarity; D003638:Deafness / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology; D018072:Hair Cells, Auditory, Outer / Q000473:pathology* / Q000503:physiopathology; D018069:Hair Cells, Vestibular / Q000473:pathology; D006801:Humans; D015640:Ion Channel Gating; D051656:KCNQ Potassium Channels / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D018408:Patch-Clamp Techniques; D013569:Synapses / Q000473:pathology
chemical_list: D051656:KCNQ Potassium Channels; C117367:KCNQ4 protein, human; C492167:Kcnq4 protein, mouse