The His723Arg (H723R) mutation in SLC26A4, encoding pendrin, is the most prevalent mutation in East Asia, resulting in DFNB4, an autosomal recessive type of genetic hearing loss. Although the main pathological mechanism of H723R was identified as a protein-folding defect in pendrin, there is still no curative treatment for associated hearing loss. Here, we show that H723R-pendrin expression and activity are rescued by activation of the chaperonin DNAJC14. In vitro, DNAJC14 was activated via Japanese encephalitis virus (JEV) inoculation, and toxin-attenuated JEV rescued the surface expression and anion exchange activity of H723R-pendrin. Human H723R-pendrin transgenic mice (hH723R Tg) were established in a mouse slc26a4 knockout background, in which only hH723R-pendrin was expressed in the inner ear (Pax2-Cre dependent) to mimic human DFNB4 pathology. Crossing hH723R Tg with DNAJC14-overexpressing mice resulted in reduced cochlear hydrops and more preserved outer hair cells in the cochlea compared to those in hH723R Tg mice. Furthermore, the stria vascularis and spiral ligament were thicker and KCNJ10 expression was increased with DNAJC14 overexpression; however, hearing function and enlarged endolymphatic hydrops were not recovered. These results indicate that DNAJC14 overexpression ameliorates the cochlear degeneration caused by misfolded pendrin and might be a potential therapeutic target for DFNB4.
|Number of pages||10|
|Journal||Molecular Therapy - Methods and Clinical Development|
|Publication status||Published - 2020 Jun 12|
Bibliographical noteFunding Information:
This work was supported by the Korean Health Technology R&D Project and the Ministry of Health & Welfare, Republic of Korea ( HI16C0142 to J.J.), and by the National Research Foundation of Korea (NRF) grants funded by the Korean government ( 2017R1D1A1B03030046 to J.J. and 2016M3A9B5941215 to J.Y.C.).
This work was supported by the Korean Health Technology R&D Project and the Ministry of Health & Welfare, Republic of Korea (HI16C0142 to J.J.), and by the National Research Foundation of Korea (NRF) grants funded by the Korean government (2017R1D1A1B03030046 to J.J. and 2016M3A9B5941215 to J.Y.C.).
© 2019 The Authors
All Science Journal Classification (ASJC) codes
- Molecular Medicine
- Molecular Biology