Abstract
Mutations inactivating the potassium channel KCNQ4 (Kv7.4) lead to deafness in humans and mice. In addition to its expression in mechanosensitive hair cells of the inner ear, KCNQ4 is found in the auditory pathway and in trigeminal nuclei that convey somatosensory information. We have now detected KCNQ4 in the peripheral nerve endings of cutaneous rapidly adapting hair follicle and Meissner corpuscle mechanoreceptors from mice and humans. Electrophysiological recordings from single afferents from Kcnq4−/− mice and mice carrying a KCNQ4 mutation found in DFNA2-type monogenic dominant human hearing loss showed elevated mechanosensitivity and altered frequency response of rapidly adapting, but not of slowly adapting nor of D-hair, mechanoreceptor neurons. Human subjects from independent DFNA2 pedigrees outperformed age-matched control subjects when tested for vibrotactile acuity at low frequencies. This work describes a gene mutation that modulates touch sensitivity in mice and humans and establishes KCNQ4 as a specific molecular marker for rapidly adapting Meissner and a subset of hair follicle afferents.
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Acknowledgements
We thank P. Seidler and H. Thraenhardt for technical assistance, the DFNA2 families for their collaboration, C. Birchmeier (MDC Berlin) for the MafA antibody, M. Maurer (Charité Berlin) for human skin biopsies and B. Purfuerst for electron microscopy. Supported by an SAW (Senatsausschuss Wettbewerb) grant of the Leibniz Gemeinschaft to T.J.J. and G.R.L., the Prix Louis-Jeantet de Médecine and the Ernst-Jung Preis für Medizin to T.J.J. and grants from the Deutsche Forschungsgemeinschaft (DFG) (SFB665) to G.R.L.; additional funding (T.J.J. and G.R.L.) was provided by the DFG (Exc 257 NeuroCure).
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M.H. performed and evaluated morphological and mouse behavioral studies, examined subjects and wrote the paper; S.G.L. performed and evaluated electrophysiological experiments, designed and built psychometric tests, examined subjects and wrote the paper; V.V. did initial antibody characterization and DRG staining; C.W. established mouse behavioral studies and analyzed electron micrographs; C.W.C., E.M.D.L., M.A.M.-P. and G.A. organized human studies; T.J.J. initiated the project, designed and evaluated experiments, organized human studies and wrote the paper; G.R.L. designed and evaluated experiments and wrote the paper.
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Supplementary Video 1
z-stack movie of KCNQ4-positive nerve endings in a mouse hair follicle. (MOV 1250 kb)
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Heidenreich, M., Lechner, S., Vardanyan, V. et al. KCNQ4 K+ channels tune mechanoreceptors for normal touch sensation in mouse and man. Nat Neurosci 15, 138–145 (2012). https://doi.org/10.1038/nn.2985
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DOI: https://doi.org/10.1038/nn.2985
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