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Hair cell synaptic dysfunction, auditory fatigue and thermal sensitivity in otoferlin Ile515Thr mutants
- Source :
- EMBO Journal, Europe PubMed Central
- Publication Year :
- 2016
-
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.
- Subjects :
- 0301 basic medicine
General Immunology and Microbiology
General Neuroscience
Auditory neuropathy
Anatomy
Biology
Ribbon synapse
medicine.disease
Synaptic vesicle
General Biochemistry, Genetics and Molecular Biology
Exocytosis
Cell biology
03 medical and health sciences
030104 developmental biology
medicine.anatomical_structure
medicine
OTOF
otorhinolaryngologic diseases
Synaptopathy
Hair cell
Molecular Biology
Auditory fatigue
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- EMBO Journal, Europe PubMed Central
- Accession number :
- edsair.doi.dedup.....fb4a68569f67f04ddd50b04ebfed3c97