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

Strenzke, N., Chakrabarti, R., Al-Moyed, H., Müller, A., Hoch, G., Pangrsic, T., et al. (2016). Hair cell synaptic dysfunction, auditory fatigue and thermal sensitivity in otoferlin Ile515Thr mutants. EMBO Journal, 35(23), 2519-2535. doi:10.15252/embj.201694564.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-002B-9AD8-F Version Permalink: http://hdl.handle.net/11858/00-001M-0000-002D-2038-7
Genre: Journal Article

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 Creators:
Strenzke, N., Author
Chakrabarti, R., Author
Al-Moyed, H., Author
Müller, A., Author
Hoch, G., Author
Pangrsic, T., Author
Yamanbaeva, G., Author
Lenz, C.1, Author              
Pan, K. T.1, Author              
Auge, E., Author
Geiss-Friedlander, R., Author
Urlaub, H.1, Author              
Brose, N., Author
Wichmann, C., Author
Reisinger, E., Author
Affiliations:
1Research Group of Bioanalytical Mass Spectrometry, MPI for Biophysical Chemistry, Max Planck Society, ou_578613              

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Free keywords: Auditory neuropathy; Hair cell; Hearing loss; Otoferlin; Ribbon synapse
 Abstract: 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, 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.

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Language(s): eng - English
 Dates: 2016-10-112016-12-01
 Publication Status: Published in print
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 Table of Contents: -
 Rev. Method: Peer
 Identifiers: DOI: 10.15252/embj.201694564
 Degree: -

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Title: EMBO Journal
Source Genre: Journal
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Pages: - Volume / Issue: 35 (23) Sequence Number: - Start / End Page: 2519 - 2535 Identifier: -