Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • Vascular Malformations (Apr 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
Mutations in unfolded protein response regulator ATF6 cause hearing and vision loss syndrome
Eun-Jin Lee, … , Allen F. Ryan, Jonathan H. Lin
Eun-Jin Lee, … , Allen F. Ryan, Jonathan H. Lin
Published November 21, 2024
Citation Information: J Clin Invest. 2025;135(3):e175562. https://doi.org/10.1172/JCI175562.
View: Text | PDF
Research Article Genetics Ophthalmology Article has an altmetric score of 4

Mutations in unfolded protein response regulator ATF6 cause hearing and vision loss syndrome

  • Text
  • PDF
Abstract

Activating transcription factor 6 (ATF6) is a key regulator of the unfolded protein response (UPR) and is important for ER function and protein homeostasis in metazoan cells. Patients carrying loss-of-function ATF6 disease alleles develop the cone dysfunction disorder achromatopsia. The effect of loss of ATF6 function on other cell types, organs, and diseases in people remains unclear. Here, we report that progressive sensorineural hearing loss was a notable complaint in some patients carrying ATF6 disease alleles and that Atf6–/– mice also showed progressive auditory deficits affecting both sexes. In mice with hearing deficits, we found disorganized stereocilia on hair cells and focal loss of outer hair cells. Transcriptomics analysis of Atf6–/– cochleae revealed a marked induction of the UPR, especially through the protein kinase RNA-like endoplasmic reticulum kinase (PERK) arm. These findings identify ATF6 as an essential regulator of cochlear health and function. Furthermore, they support the idea that ATF6 inactivation in people causes progressive sensorineural hearing loss as part of a blindness-deafness genetic syndrome targeting hair cells and cone photoreceptors. Last, our genetic findings indicate that ER stress is an important pathomechanism underlying cochlear damage and hearing loss, with clinical implications for patient lifestyle modifications that minimize environmental and physiological sources of ER stress to the ear.

Authors

Eun-Jin Lee, Kyle Kim, Monica Sophia Diaz-Aguilar, Hyejung Min, Eduardo Chavez, Korina J. Steinbergs, Lance A. Safarta, Guirong Zhang, Allen F. Ryan, Jonathan H. Lin

×

Figure 1

Human ATF6 mutations are linked to hearing loss.

Options: View larger image (or click on image) Download as PowerPoint
Human ATF6 mutations are linked to hearing loss.
(A) Pedigree of the fam...
(A) Pedigree of the family carrying the point mutation (c.970C>T, p.Arg324Cys) and audiograms from individuals aged 52, 43, and 49 years showing moderate high-frequency hearing loss in both the right (red line) and left (blue line) ears. (B) Audiograms from patient II:1 at ages 40 and 52 years revealed progressive high-frequency hearing loss. (C) Audiograms from patient II:2 at ages 39 and 43 years show a similar hearing loss progression. (D) Audiograms from patient II:3 at ages 31 and 49 years show some progression of high-frequency hearing loss. (E) Pedigree of the family carrying the point mutation (c.1699T>A, p.Tyr567Asn, age 14 years) shows severe low- to high-frequency hearing loss in both the right (red line) and left (blue line) ears. Green line indicates a normal hearing threshold.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts

Posted by 4 X users
On 1 Facebook pages
Referenced by 2 Bluesky users
1 readers on Mendeley
See more details