Dept. of Otolaryngology, University of Kentucky Medical School, Lexington, KY 40536, USA.; Department of Otolaryngology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, PR China.
Dept. of Otolaryngology, University of Kentucky Medical School, Lexington, KY 40536, USA.
Biochem Biophys Res Commun. 2014 May 23;448(1):28-32. doi: 10.1016/j.bbrc.2014.04.016. Epub 2014 Apr 13.
Connexin 26 (Cx26, GJB2) mutations are the major cause of hereditary deafness and are responsible for >50% of nonsyndromic hearing loss. Mouse models show that Cx26 deficiency can cause congenital deafness with cochlear developmental disorders, hair cell degeneration, and the reduction of endocochlear potential (EP) and active cochlear amplification. However, the underlying deafness mechanism still remains undetermined. Our previous studies revealed that hair cell degeneration is not a primary cause of hearing loss. In this study we investigated the role of EP reduction in Cx26 deficiency-induced deafness. We found that the EP reduction is not associated with congenital deafness in Cx26 knockout (KO) mice. The threshold of auditory brainstem response (ABR) in Cx26 KO mice was even greater than 110 dB SPL, demonstrating complete hearing loss. However, the EP in Cx26 KO mice varied and not completely abolished. In some cases, the EP could still remain at higher levels (>70 mV). We further found that the deafness in Cx26 KO mice is associated with cochlear developmental disorders. Deletion of Cx26 in the cochlea before postnatal day 5 (P5) could cause congenital deafness. The cochlea had developmental disorders and the cochlear tunnel was not open. However, no congenital deafness was found when Cx26 was deleted after P5. The cochlea also displayed normal development and the cochlear tunnel was open normally. These data suggest that congenital deafness induced by Cx26 deficiency is not determined by EP reduction and may result from cochlear developmental disorders.
间隙连接蛋白 26（Cx26，GJB2）突变是遗传性耳聋的主要原因，占非综合征性听力损失的>50%。小鼠模型表明，Cx26 缺乏可导致先天性耳聋，伴有耳蜗发育障碍、毛细胞变性以及内淋巴液（EP）和主动耳蜗放大减少。然而，潜在的耳聋机制仍未确定。我们之前的研究表明，毛细胞变性不是听力损失的主要原因。在本研究中，我们研究了 EP 减少在 Cx26 缺乏诱导的耳聋中的作用。我们发现 EP 减少与 Cx26 敲除（KO）小鼠的先天性耳聋无关。Cx26 KO 小鼠的听觉脑干反应（ABR）阈值甚至大于 110 dB SPL，表明完全耳聋。然而，Cx26 KO 小鼠中的 EP 变化且并未完全消除。在某些情况下，EP 仍可保持在较高水平（>70 mV）。我们进一步发现，Cx26 KO 小鼠的耳聋与耳蜗发育障碍有关。在出生后第 5 天（P5）之前在耳蜗中删除 Cx26 可导致先天性耳聋。耳蜗发育障碍，耳蜗隧道未开放。然而，在 P5 之后删除 Cx26 时并未发现先天性耳聋。耳蜗也正常发育，耳蜗隧道正常开放。这些数据表明，Cx26 缺乏引起的先天性耳聋不是由 EP 减少决定的，可能是由耳蜗发育障碍引起的。
