title: Hair cell synaptic dysfunction, auditory fatigue and thermal sensitivity in otoferlin Ile515Thr mutants.
abstract: The multi-C2domain protein otoferlin is required for hearing and mutated in human deafness. Some OTOF mutations cause a mild elevation of auditory thresholds but strong impairment of speech perception. At elevated body temperature, hearing is lost. Mice homozygous for one of these mutations, OtofI515T/I515T, exhibit a moderate hearing impairment involving enhanced adaptation to continuous or repetitive sound stimulation. In OtofI515T/I515Tinner hair cells (IHCs), otoferlin levels are diminished by 65%, and synaptic vesicles are enlarged. Exocytosis during prolonged stimulation is strongly reduced. This indicates that otoferlin is critical for the reformation of properly sized and fusion-competent synaptic vesicles. Moreover, we found sustained exocytosis and sound encoding to scale with the amount of otoferlin at the plasma membrane. We identified a 20 amino acid motif including an RXR motif, presumably present in human but not in mouse otoferlin, which reduces the plasma membrane abundance of Ile515Thr-otoferlin. Together, this likely explains the auditory synaptopathy at normal temperature and the temperature-sensitive deafness in humans carrying the Ile515Thr mutation.
authors.affiliation: Auditory Systems Physiology Group, Department for Otolaryngology and InnerEarLab, University Medical Center Göttingen, Göttingen, Germany nstrenzke@med.uni-goettingen.de carolin.wichmann@med.uni-goettingen.de ellen.reisinger@med.uni-goettingen.de.|Collaborative Research Center 889 "Cellular Mechanisms of Sensory Processing", Göttingen, Germany.
authors.forename: Nicola
authors.initials: N
authors.lastname: Strenzke
authors.affiliation: Collaborative Research Center 889 "Cellular Mechanisms of Sensory Processing", Göttingen, Germany.|Molecular Architecture of Synapses Group, Institute for Auditory Neuroscience and InnerEarLab, University Medical Center Göttingen and Max Planck Institute of Experimental Medicine, Göttingen, Germany.|Göttingen Graduate School for Neurosciences, Biophysics, and Molecular Biosciences, Göttingen, Germany.
authors.forename: Rituparna
authors.initials: R
authors.lastname: Chakrabarti
authors.affiliation: Göttingen Graduate School for Neurosciences, Biophysics, and Molecular Biosciences, Göttingen, Germany.|Molecular Biology of Cochlear Neurotransmission Group, Department for Otolaryngology and InnerEarLab, University Medical Center Göttingen, Göttingen, Germany.
authors.forename: Hanan
authors.initials: H
authors.lastname: Al-Moyed
authors.affiliation: Collaborative Research Center 889 "Cellular Mechanisms of Sensory Processing", Göttingen, Germany.|Göttingen Graduate School for Neurosciences, Biophysics, and Molecular Biosciences, Göttingen, Germany.|Molecular Biology of Cochlear Neurotransmission Group, Department for Otolaryngology and InnerEarLab, University Medical Center Göttingen, Göttingen, Germany.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Müller
authors.affiliation: Institute for Auditory Neuroscience and InnerEarLab, University Medical Center Göttingen and German Primate Center, Göttingen, Germany.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Hoch
authors.affiliation: Collaborative Research Center 889 "Cellular Mechanisms of Sensory Processing", Göttingen, Germany.|Synaptic Physiology of Mammalian Vestibular Hair Cells Group, Institute for Auditory Neuroscience and InnerEarLab, University Medical Center Göttingen and Max Planck Institute of Experimental Medicine, Göttingen, Germany.
authors.forename: Tina
authors.initials: T
authors.lastname: Pangrsic
authors.affiliation: Auditory Systems Physiology Group, Department for Otolaryngology and InnerEarLab, University Medical Center Göttingen, Göttingen, Germany.|Collaborative Research Center 889 "Cellular Mechanisms of Sensory Processing", Göttingen, Germany.|Göttingen Graduate School for Neurosciences, Biophysics, and Molecular Biosciences, Göttingen, Germany.
authors.forename: Gulnara
authors.initials: G
authors.lastname: Yamanbaeva
authors.affiliation: Bioanalytical Mass Spectrometry Group, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany.|Bioanalytics, Institute of Clinical Chemistry, University Medical Center Göttingen, Göttingen, Germany.
authors.forename: Christof
authors.initials: C
authors.lastname: Lenz
authors.affiliation: Bioanalytical Mass Spectrometry Group, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany.
authors.forename: Kuan-Ting
authors.initials: KT
authors.lastname: Pan
authors.affiliation: Auditory Systems Physiology Group, Department for Otolaryngology and InnerEarLab, University Medical Center Göttingen, Göttingen, Germany.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Auge
authors.affiliation: Department of Molecular Biology, University Medical Center Göttingen, Göttingen, Germany.
authors.forename: Ruth
authors.initials: R
authors.lastname: Geiss-Friedlander
authors.affiliation: Collaborative Research Center 889 "Cellular Mechanisms of Sensory Processing", Göttingen, Germany.|Bioanalytical Mass Spectrometry Group, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany.|Bioanalytics, Institute of Clinical Chemistry, University Medical Center Göttingen, Göttingen, Germany.
authors.forename: Henning
authors.initials: H
authors.lastname: Urlaub
authors.affiliation: Collaborative Research Center 889 "Cellular Mechanisms of Sensory Processing", Göttingen, Germany.|Department of Molecular Neurobiology, Max Planck Institute of Experimental Medicine, Göttingen, Germany.
authors.forename: Nils
authors.initials: N
authors.lastname: Brose
authors.affiliation: Collaborative Research Center 889 "Cellular Mechanisms of Sensory Processing", Göttingen, Germany nstrenzke@med.uni-goettingen.de carolin.wichmann@med.uni-goettingen.de ellen.reisinger@med.uni-goettingen.de.|Molecular Architecture of Synapses Group, Institute for Auditory Neuroscience and InnerEarLab, University Medical Center Göttingen and Max Planck Institute of Experimental Medicine, Göttingen, Germany.
authors.forename: Carolin
authors.initials: C
authors.lastname: Wichmann
authors.affiliation: Collaborative Research Center 889 "Cellular Mechanisms of Sensory Processing", Göttingen, Germany nstrenzke@med.uni-goettingen.de carolin.wichmann@med.uni-goettingen.de ellen.reisinger@med.uni-goettingen.de.|Molecular Biology of Cochlear Neurotransmission Group, Department for Otolaryngology and InnerEarLab, University Medical Center Göttingen, Göttingen, Germany.|Department of Molecular Neurobiology, Max Planck Institute of Experimental Medicine, Göttingen, Germany.
authors.forename: Ellen
authors.identifier: 0000-0003-3739-7569
authors.initials: E
authors.lastname: Reisinger
mesh_terms: D000818:Animals; D001305:Auditory Fatigue; D005089:Exocytosis; D006198:Hair Cells, Auditory / Q000502:physiology*; D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D050505:Mutant Proteins / Q000737:chemistry / Q000235:genetics*; D020125:Mutation, Missense; D055550:Protein Stability / Q000528:radiation effects*; D013569:Synapses / Q000378:metabolism*; D013696:Temperature
chemical_list: D008565:Membrane Proteins; D050505:Mutant Proteins; C118457:OTOF protein, human; C516233:otoferlin protein, mouse
keywords: auditory neuropathy; hair cell; hearing loss; otoferlin; ribbon synapse