Mice with altered KCNQ4 K+ channels implicate sensory outer hair cells in human progressive deafness.
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.
Kharkovets
Tatjana
T
Zentrum für Molekulare Neurobiologie, ZMNH, Universität Hamburg, Hamburg, Germany.
Dedek
Karin
K
Maier
Hannes
H
Schweizer
Michaela
M
Khimich
Darina
D
Nouvian
Régis
R
Vardanyan
Vitya
V
Leuwer
Rudolf
R
Moser
Tobias
T
Jentsch
Thomas J
TJ
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
D051656:KCNQ Potassium Channels; C117367:KCNQ4 protein, human; C492167:Kcnq4 protein, mouse