Abnormal Cochlear Potentials from Deaf Patients with Mutations in the Otoferlin Gene
Abnormal Cochlear Potentials from Deaf Patients with Mutations in the Otoferlin Gene
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DOI：
10.1007/s10162-009-0181-z
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发表时间：
2009-12-01
影响因子：
2.4
通讯作者：
Starr, Arnold
中科院分区：
文献类型：
--
作者：
Santarelli, Rosamaria;del Castillo, Ignacio;Starr, Arnold
Otoferlin参与内毛细胞(IHC)和听神经纤维之间突触的神经递质释放，OTOF基因的突变会导致严重的听力损失。用经鼓室电子耳蜗术记录了4例Otoferlin(OTOF)突变儿童的异常声诱发耳蜗电，以评价IHC神经递质异常释放对人体的生理影响。受试者严重失聪，听觉脑干反应缺失，耳声发射保存与听神经病一致。其中2例为突变c.2732_2735dupAGCT和p.Ala964Glu的复合杂合子，1例为突变p.Phe1795Cys的纯合子，1例为突变外显子16的c.1609delG和外显子18的c.1966delC的复合杂合子。除一耳外，其余耳均记录到正常波幅的微音器。取消CM后，与对照组相比，耳蜗电电位呈负极性，波幅降低，持续时间延长。这些耳蜗电位被记录到比行为阈值低50-90分贝，而对照组的耳蜗电位与行为阈值密切相关。在潜伏期正常的8耳中，有5耳可检测到总和电位，而听神经复合动作电位不存在或波幅较低。高频率的刺激降低了延长的电位的幅度和持续时间，这与神经生成一致。本研究提示，OTOF基因突变患者的机械-电转导和耳蜗声放大功能正常。低波幅延长的负电位与神经递质释放减少，导致树突状细胞异常激活和听神经放电障碍相一致。
Otoferlin is involved in neurotransmitter release at the synapse between inner hair cells (IHCs) and auditory nerve fibres, and mutations in the OTOF gene result in severe to profound hearing loss. Abnormal sound-evoked cochlear potentials were recorded with transtympanic electrocochleography from four children with otoferlin (OTOF) mutations to evaluate physiological effects in humans of abnormal neurotransmitter release from IHCs. The subjects were profoundly deaf with absent auditory brainstem responses and preserved otoacoustic emissions consistent with auditory neuropathy. Two children were compound heterozygotes for mutations c.2732_2735dupAGCT and p.Ala964Glu; one subject was homozygous for mutation p.Phe1795Cys, and one was compound heterozygote for two novel mutations c.1609delG in exon 16 and c.1966delC in exon 18. Cochlear potentials evoked by clicks from 60 to 120 dB peak equivalent sound pressure level were compared to recordings obtained from 16 normally hearing children. Cochlear microphonic (CM) was recorded with normal amplitudes from all but one ear. After cancelling CM, cochlear potentials were of negative polarity with reduced amplitude and prolonged duration compared to controls. These cochlear potentials were recorded as low as 50-90 dB below behavioural thresholds in contrast to the close correlation in controls between cochlear potentials and behavioural threshold. Summating potential was identified in five out of eight ears with normal latency whilst auditory nerve compound action potentials were either absent or of low amplitude. Stimulation at high rates reduced amplitude and duration of the prolonged potentials, consistent with neural generation. This study suggests that mechano-electrical transduction and cochlear amplification are normal in patients with OTOF mutations. The low-amplitude prolonged negative potentials are consistent with decreased neurotransmitter release resulting in abnormal dendritic activation and impairment of auditory nerve firing.