Hair cell synaptic dysfunction, auditory fatigue and thermal sensitivity in otoferlin Ile515Thr mutants

• DOI: 10.15252/embj.201694564
• Publication Date: 2016-10-12T00:39:59Z
• Authors: Nicola Strenzke; Rituparna Chakrab...; Hanan Al‐Moyed; Alexandra Müller; Gerhard Hoch; Tina Pangrsic; Gulnara Yamanbaeva; Christof Lenz; Kuan‐Ting Pan; Elisabeth Auge; Ruth Geiss‐Friedl...; Henning Urlaub; Nils Brose; Carolin Wichmann; Ellen Reisinger
• Keywords: 0303 health sciences; Protein Stability; Mutation, Missense; Temperature; Membrane Proteins; Exocytosis; Mice; 03 medical and health sciences; Hair Cells, Auditory; Synapses; Animals; Humans; Mutant Proteins; Auditory Fatigue

AbstractThe multi‐C2 domain 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/I515T inner 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.