Zhu Y, Chen J, Liang C, Zong L, Chen J, Jones R O, Zhao H-B
Dept. of Otolaryngology, University of Kentucky Medical School, Lexington, KY 40536, United States.
Dept. of Otolaryngology, University of Kentucky Medical School, Lexington, KY 40536, United States.
Neuroscience. 2015 Jan 22;284:719-729. doi: 10.1016/j.neuroscience.2014.10.061. Epub 2014 Nov 5.
Connexin26 (Cx26, GJB2) mutations account for >50% of nonsyndromic hearing loss. The deafness is not always congenital. A large group of these patients (∼30%) demonstrate a late-onset hearing loss, starting in childhood. They have normal hearing early in life and are therefore good candidates for applying protective and therapeutic interventions. However, the underlying deafness mechanism is unclear. In this study, we used a time-controlled, inducible gene knockout technique to knockout Cx26 expression in the cochlea after birth. We found that deletion of Cx26 after postnatal day 5 (P5) in mice could lead to late-onset hearing loss. Similar to clinical observations, the mice demonstrated progressive, mild to moderate hearing loss. The hearing loss initiated at high frequencies and then extended to the middle- and low-frequency range. The cochlea showed normal development and had no apparent hair cell loss. However, distortion product otoacoustic emission (DPOAE) was reduced. The reduction was also progressive and large at high-frequencies. Consistent with DPOAE reduction, we found that outer hair cell electromotility-associated nonlinear capacitance was shifted to the right and the slope of voltage dependence was reduced. The endocochlear potential was reduced in Cx26 conditional knockout (cKO) mice but the reduction was not associated with progressive hearing loss. These data suggest that Cx26 deficiency may impair active cochlear amplification leading to late-onset hearing loss. Our study also helps develop newer protective and therapeutic interventions to this common nonsyndromic hearing loss.
连接蛋白26（Cx26，GJB2）突变导致超过50%的非综合征性听力损失。耳聋并非总是先天性的。这类患者中有很大一部分（约30%）表现为迟发性听力损失，始于儿童期。他们在生命早期听力正常，因此是应用保护性和治疗性干预措施的理想对象。然而，潜在的耳聋机制尚不清楚。在本研究中，我们使用了一种时间可控的诱导基因敲除技术，在出生后敲除耳蜗中的Cx26表达。我们发现，小鼠出生后第5天（P5）后缺失Cx26会导致迟发性听力损失。与临床观察结果相似，小鼠表现出进行性的轻度至中度听力损失。听力损失始于高频，然后扩展到中低频范围。耳蜗显示发育正常，没有明显的毛细胞损失。然而，畸变产物耳声发射（DPOAE）降低。这种降低也是进行性的，在高频时幅度较大。与DPOAE降低一致，我们发现外毛细胞电运动相关的非线性电容向右移动，电压依赖性斜率降低。Cx26条件性敲除（cKO）小鼠的内淋巴电位降低，但这种降低与进行性听力损失无关。这些数据表明，Cx26缺乏可能会损害耳蜗的主动放大功能，导致迟发性听力损失。我们的研究也有助于开发针对这种常见的非综合征性听力损失的新型保护性和治疗性干预措施。
