Hair cell synaptic dysfunction, auditory fatigue and thermal sensitivity in otoferlin Ile515Thr mutants
Hair cell synaptic dysfunction, auditory fatigue and thermal sensitivity in otoferlin Ile515Thr mutants
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DOI：
10.15252/embj.201694564
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发表时间：
2016-12-01
期刊：
影响因子：
11.4
通讯作者：
Reisinger, Ellen
中科院分区：
文献类型：
--
作者：
Strenzke, Nicola;Chakrabarti, Rituparna;Reisinger, Ellen
多C-2结构域蛋白otoferlin是听力所需的，并在人类耳聋中发生突变。一些OTOF突变导致听觉阈值轻度升高，但言语感知严重受损。体温升高时，听力丧失。这些突变之一的小鼠Otof（I515 T/I515 T）纯合子表现出中度听力障碍，包括对连续或重复声音刺激的适应性增强。在Otof（I515 T/I515 T）内毛细胞（IHC）中，otoferlin水平降低65%，突触囊泡扩大。长时间刺激期间的胞吐作用强烈减少。这表明，otoferlin是至关重要的重组适当大小和融合能力的突触囊泡。此外，我们发现持续的胞吐和声音编码与质膜上的otoferlin的量成比例。我们确定了一个20个氨基酸的基序，包括RXR基序，推测存在于人类，但不存在于小鼠otoferlin，这减少了质膜丰度的Ile 515 Thr-otoferlin。总之，这可能解释了正常温度下的听觉突触病和携带Ile 515 Thr突变的人类的温度敏感性耳聋。
The multi-C-2 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.