A deafness mechanism of digenic Cx26 (GJB2) and Cx30 (GJB6) mutations: Reduction of endocochlear potential by impairment of heterogeneous gap junctional function in the cochlear lateral wall

Neurobiology of Disease

Hong-Bo Zhao¹  Yan Zhu²  Jin Chen³  Chun Liang⁴  Ling Mei⁵  Raleigh O. Jones⁵  Liang Zong⁵ 

[1] Department of Otolaryngology, Chinese PLA General Hospital, 28 Fuxing Road, Beijing 100853, PR China;;Department of Otolaryngology, Tongji Hospital, Huazhong University of Science &Department of Otolaryngology, Xinhua Hospital, Shanghai Jiao Tong University Medical School, Shanghai 200092, PR China;Technology, 1095 Jiefang Avenue, Wuhan 430030, PR China;Department of Otolaryngology, University of Kentucky Medical Center, 800 Rose Street, Lexington, KY 40536, USA;

关键词: Gap junction;    Connexin;    Cx26;    Cx30;    Endocochlear potential;    Deafness;   

DOI  :  

来源: DOAJ

【 摘 要 】

Digenic Connexin26 (Cx26, GJB2) and Cx30 (GJB6) heterozygous mutations are the second most frequent cause of recessive deafness in humans. However, the underlying deafness mechanism remains unclear. In this study, we created different double Cx26 and Cx30 heterozygous (Cx26+/−/Cx30+/−) mouse models to investigate the underlying pathological changes and deafness mechanism. We found that double Cx26+/−/Cx30+/− heterozygous mice had hearing loss. Endocochlear potential (EP), which is a driving force for hair cells producing auditory receptor current, was reduced. However, unlike Cx26 homozygous knockout (Cx26−/−) mice, the cochlea in Cx26+/−/Cx30+/− mice displayed normal development and had no apparent hair cell degeneration. Gap junctions (GJs) in the cochlea form two independent networks: the epithelial cell GJ network in the organ of Corti and the connective tissue GJ network in the cochlear lateral wall. We further found that double heterozygous deletion of Cx26 and Cx30 in the epithelial cells did not reduce EP and had normal hearing, suggesting that Cx26+/−/Cx30+/− may mainly impair gap junctional functions in the cochlear lateral wall and lead to EP reduction and hearing loss. Most of Cx26 and Cx30 in the cochlear lateral wall co-expressed in the same gap junctional plaques. Moreover, sole Cx26+/− or Cx30+/− heterozygous mice had no hearing loss. These data further suggest that digenic Cx26 and Cx30 mutations may impair heterozygous coupling of Cx26 and Cx30 in the cochlear lateral wall to reduce EP, thereby leading to hearing loss.

【 授权许可】

Unknown