Wingard Jeffrey C, Zhao Hong-Bo
Department of Otolaryngology, University of Kentucky Medical Center , Lexington, KY , USA.
Front Cell Neurosci. 2015 May 29;9:202. doi: 10.3389/fncel.2015.00202. eCollection 2015.
Hearing loss due to mutations in the connexin gene family, which encodes gap junctional proteins, is a common form of hereditary deafness. In particular, connexin 26 (Cx26, GJB2) mutations are responsible for ~50% of non-syndromic hearing loss, which is the highest incidence of genetic disease. In the clinic, Cx26 mutations cause various auditory phenotypes ranging from profound congenital deafness at birth to mild, progressive hearing loss in late childhood. Recent experiments demonstrate that congenital deafness mainly results from cochlear developmental disorders rather than hair cell degeneration and endocochlear potential reduction, while late-onset hearing loss results from reduction of active cochlear amplification, even though cochlear hair cells have no connexin expression. However, there is no apparent, demonstrable relationship between specific changes in connexin (channel) functions and the phenotypes of mutation-induced hearing loss. Moreover, new experiments further demonstrate that the hypothesized K(+)-recycling disruption is not a principal deafness mechanism for connexin deficiency induced hearing loss. Cx30 (GJB6), Cx29 (GJC3), Cx31 (GJB3), and Cx43 (GJA1) mutations can also cause hearing loss with distinct pathological changes in the cochlea. These new studies provide invaluable information about deafness mechanisms underlying connexin mutation-induced hearing loss and also provide important information for developing new protective and therapeutic strategies for this common deafness. However, the detailed cellular mechanisms underlying these pathological changes remain unclear. Also, little is known about specific mutation-induced pathological changes in vivo and little information is available for humans. Such further studies are urgently required.
连接蛋白基因家族编码间隙连接蛋白，该家族突变导致的听力损失是遗传性耳聋的常见形式。特别是，连接蛋白26（Cx26，GJB2）突变导致约50%的非综合征性听力损失，这是遗传疾病中发病率最高的。在临床上，Cx26突变会导致各种听觉表型，从出生时的严重先天性耳聋到儿童晚期的轻度、进行性听力损失。最近的实验表明，先天性耳聋主要是由耳蜗发育障碍引起的，而不是毛细胞退化和内淋巴电位降低，而迟发性听力损失是由耳蜗主动放大功能降低引起的，尽管耳蜗毛细胞没有连接蛋白表达。然而，连接蛋白（通道）功能的特定变化与突变诱导的听力损失表型之间没有明显的、可证明的关系。此外，新的实验进一步表明，假设的K(+)循环破坏不是连接蛋白缺陷诱导的听力损失的主要耳聋机制。Cx30（GJB6）、Cx29（GJC3）、Cx31（GJB3）和Cx43（GJA1）突变也可导致听力损失，耳蜗有明显的病理变化。这些新研究提供了关于连接蛋白突变诱导听力损失的耳聋机制的宝贵信息，也为开发针对这种常见耳聋的新保护和治疗策略提供了重要信息。然而，这些病理变化背后的详细细胞机制仍不清楚。此外，关于体内特定突变诱导的病理变化知之甚少，人类方面的信息也很少。迫切需要进行此类进一步研究。
