Research Paper Volume 11, Issue 18 pp 7416—7441

Hearing consequences in Gjb2 knock-in mice: implications for human p.V37I mutation

Xin Lin1,2,3, *, , Gen Li1,2,3, *, , Yu Zhang1,2,3, *, , Jingjing Zhao1,2,3, , Jiawen Lu1,2,3, , Yunge Gao1,2,3, , Huihui Liu1,2,3, , Geng-Lin Li1,2,3, , Tao Yang1,2,3, , Lei Song1,2,3, , Hao Wu1,2,3, ,

  • 1 Department of Otolaryngology-Head and Neck Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China
  • 2 Ear Institute, Shanghai Jiao Tong University School of Medicine, Shanghai 200125, China
  • 3 Shanghai Key Laboratory of Translational Medicine on Ear and Nose diseases, Shanghai 200125, China
* Equal contribution

Received: July 15, 2019       Accepted: August 22, 2019       Published: September 27, 2019
How to Cite

Copyright © 2019 Lin et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Human p.V37I mutation of GJB2 gene was strongly correlated with late-onset progressive hearing loss, especially among East Asia populations. We generated a knock-in mouse model based on human p.V37I variant (c.109G>A) that recapitulated the human phenotype. Cochlear pathology revealed no significant hair cell loss, stria vascularis atrophy or spiral ganglion neuron loss, but a significant change in the length of gap junction plaques, which may have contributed to the observed mild endocochlear potential (EP) drop in homozygous mice lasting lifetime. The cochlear amplification in homozygous mice was compromised, but outer hair cells’ function remained unchanged, indicating that the reduced amplification was EP- rather than prestin-generated. In addition to ABR threshold elevation, ABR wave I latencies were also prolonged in aged homozygous animals. We found in homozygous IHCs a significant increase in ICa but no change in Ca2+ efficiency in triggering exocytosis. Environmental insults such as noise exposure, middle ear injection of KCl solution and systemic application of furosemide all exacerbated the pathological phenotype in homozygous mice. We conclude that this Gjb2 mutation-induced hearing loss results from 1) reduced cochlear amplifier caused by lowered EP, 2) IHCs excitotoxicity associated with potassium accumulation around hair cells, and 3) progression induced by environmental insults.


GJ: gap junction; EP: endocochlear potential; Cx: connexin; SV: Stria Vascularis; SGN: spiral ganglion neuron; NLC: nonlinear capacitance; FMTC: forward masking tuning curves; △Cm: capacitance change; Q: calcium charge; NKCC: Na-K-Cl cotransporter.