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

卷:108

Article

Mei, Ling^1,2  Chen, Jin^1,3  Zong, Liang^1,4  Zhu, Yan¹  Liang, Chun¹  Jones, Raleigh O.¹  Zhao, Hong-Bo¹ 

[1] Univ Kentucky, Med Ctr, Dept Otolaryngol, 800 Rose St, Lexington, KY 40536 USA

[2] Shanghai Jiao Tong Univ, Med Sch, Dept Otolaryngol, Xinhua Hosp, Shanghai 200092, Peoples R China

[3] Huazhong Univ Sci & Technol, Tongji Hosp, Dept Otolaryngol, 1095 Jiefang Ave, Wuhan 430030, Hubei, Peoples R China

[4] Chinese Peoples Liberat Army Gen Hosp, Dept Otolaryngol, 28 Fuxing Rd, Beijing 100853, Peoples R China

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

DOI  :  10.1016/j.nbd.2017.08.002

来源: Elsevier

【 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. (C) 2017 Elsevier Inc. All rights reserved.

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