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DNAJC14 Ameliorates Inner Ear Degeneration in the DFNB4 Mouse Model

Authors
 Hye Ji Choi  ;  Hyun Jae Lee  ;  Jin Young Choi  ;  Ik Hyun Jeon  ;  Byunghwa Noh  ;  Sushil Devkota  ;  Han-Woong Lee  ;  Seong Kug Eo  ;  Jae Young Choi  ;  Min Goo Lee  ;  Jinsei Jung 
Citation
 MOLECULAR THERAPY-METHODS & CLINICAL DEVELOPMENT, Vol.17(1) : 188-197, 2020-06 
Journal Title
 MOLECULAR THERAPY-METHODS & CLINICAL DEVELOPMENT 
Issue Date
2020-06
Keywords
DFNB4 ; DNAJC14 ; H723R ; Pendred syndrome ; chaperone ; flavivirus ; genetic hearing loss ; pendrin ; slc26a4 ; unconventional secretion
Abstract
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.
Files in This Item:
T202000406.pdf Download
DOI
10.1016/j.omtm.2019.11.019
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Pharmacology (약리학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Ophthalmology (안과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Otorhinolaryngology (이비인후과학교실) > 1. Journal Papers
Yonsei Authors
Lee, Min Goo(이민구) ORCID logo https://orcid.org/0000-0001-7436-012X
Jun, Ik Hyun(전익현) ORCID logo https://orcid.org/0000-0002-2160-1679
Jung, Jinsei(정진세) ORCID logo https://orcid.org/0000-0003-1906-6969
Choi, Jae Young(최재영) ORCID logo https://orcid.org/0000-0001-9493-3458
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/175938
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