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.
journal_name
Mol Ther Methods Clin Devjournal_title
Molecular therapy. Methods & clinical developmentauthors
Choi HJ,Lee HJ,Choi JY,Jeon IH,Noh B,Devkota S,Lee HW,Eo SK,Choi JY,Lee MG,Jung Jdoi
10.1016/j.omtm.2019.11.019subject
Has Abstractpub_date
2019-11-30 00:00:00pages
188-197issn
2329-0501pii
S2329-0501(19)30144-5journal_volume
17pub_type
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