| Autor: |
Strenzke, Nicola, Chakrabarti, Rituparna, Al‐Moyed, Hanan, Müller, Alexandra, Hoch, Gerhard, Pangrsic, Tina, Yamanbaeva, Gulnara, Lenz, Christof, Pan, Kuan‐Ting, Auge, Elisabeth, Geiss‐Friedlander, Ruth, Urlaub, Henning, Brose, Nils, Wichmann, Carolin, Reisinger, Ellen |
| Předmět: |
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| Zdroj: |
EMBO Journal; 12/1/2016, Vol. 35 Issue 23, p2519-2535, 17p, 8 Graphs |
| Abstrakt: |
The 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, Otof I515T/ I515T , exhibit a moderate hearing impairment involving enhanced adaptation to continuous or repetitive sound stimulation. In Otof I515T/ 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. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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