A deafness-blindness syndrome results from ATF6-based disruption of the unfolded protein response
Yuvraj Joshi, Jeffrey N. Savas
Yuvraj Joshi, Jeffrey N. Savas
Published February 3, 2025
Citation Information: J Clin Invest. 2025;135(3):e188708. https://doi.org/10.1172/JCI188708.
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Commentary

A deafness-blindness syndrome results from ATF6-based disruption of the unfolded protein response

Abstract

Sensorineural hearing loss (SNHL) is the most prevalent form of permanent hearing impairment, arising from factors such as aging, exposure to loud noise, disease, ototoxic medications, and genetic mutations. Despite extensive research, effective treatments or cures for SNHL remain elusive. In this issue of the JCI, Lee et al. reveal a link between mutations in ATF6 and SNHL in patients with achromatopsia. The study also shows that Atf6-deficient (Atf6–/–) mice exhibit disorganized stereocilia and age-related loss of outer hair cells. Additionally, the researchers show that Atf6 is critical for cochlear hair cell function. Mice lacking Atf6 expression experienced ER stress, which ultimately led to SNHL. Collectively, these findings enhance our understanding of the emerging role of protein homeostasis and ER stress in the pathogenesis of SNHL.

Authors

Yuvraj Joshi, Jeffrey N. Savas

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Figure 1

A deafness-blindness syndrome results from ATF6-mediated disruption of the UPR, leading to altered hair cell stereocilia and cell death.

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A deafness-blindness syndrome results from ATF6-mediated disruption of t...
In human and mouse cochleae lacking expression of ATF6, OHC dysfunction and death occur, with hearing loss progressively worsening in middle age. In the absence of Atf6 expression in mice, genes involved in ER stress, the UPR, and actin filaments (e.g., stereocilia) are dysregulated. ATF6 loss results in activation of the UPR and upregulation of genes involved in the ERAD pathway. These findings suggest that the human and mouse phenotypes are linked to compromised cochlear proteostasis. However, the exact mechanism connecting altered gene expression, stereocilia deformation, and OHC death remains unclear. IRE1, inositol-requiring enzyme 1.