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ResearchIn-Press PreviewGeneticsOphthalmology Open Access | 10.1172/JCI175562

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

Eun-Jin Lee,1 Kyle Kim,1 Monica Sophia Diaz-Aguilar,1 Hyejung Min,3 Eduardo Chavez,4 Korina J. Steinbergs,1 Lance A. Safarta,1 Guirong Zhang,1 Allen F. Ryan,4 and Jonathan H. Lin1

1Pathology, Stanford University School of Medicine, Stanford, United States of America

2Pathology, Stanford University School of Medicine, Standford, United States of America

3Ophthalmology, Stanford University School of Medicine, Stanford, United States of America

4Departments of Otolaryngology and Neuroscience, University of California San Diego, La Jolla, United States of America

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1Pathology, Stanford University School of Medicine, Stanford, United States of America

2Pathology, Stanford University School of Medicine, Standford, United States of America

3Ophthalmology, Stanford University School of Medicine, Stanford, United States of America

4Departments of Otolaryngology and Neuroscience, University of California San Diego, La Jolla, United States of America

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1Pathology, Stanford University School of Medicine, Stanford, United States of America

2Pathology, Stanford University School of Medicine, Standford, United States of America

3Ophthalmology, Stanford University School of Medicine, Stanford, United States of America

4Departments of Otolaryngology and Neuroscience, University of California San Diego, La Jolla, United States of America

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1Pathology, Stanford University School of Medicine, Stanford, United States of America

2Pathology, Stanford University School of Medicine, Standford, United States of America

3Ophthalmology, Stanford University School of Medicine, Stanford, United States of America

4Departments of Otolaryngology and Neuroscience, University of California San Diego, La Jolla, United States of America

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1Pathology, Stanford University School of Medicine, Stanford, United States of America

2Pathology, Stanford University School of Medicine, Standford, United States of America

3Ophthalmology, Stanford University School of Medicine, Stanford, United States of America

4Departments of Otolaryngology and Neuroscience, University of California San Diego, La Jolla, United States of America

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1Pathology, Stanford University School of Medicine, Stanford, United States of America

2Pathology, Stanford University School of Medicine, Standford, United States of America

3Ophthalmology, Stanford University School of Medicine, Stanford, United States of America

4Departments of Otolaryngology and Neuroscience, University of California San Diego, La Jolla, United States of America

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1Pathology, Stanford University School of Medicine, Stanford, United States of America

2Pathology, Stanford University School of Medicine, Standford, United States of America

3Ophthalmology, Stanford University School of Medicine, Stanford, United States of America

4Departments of Otolaryngology and Neuroscience, University of California San Diego, La Jolla, United States of America

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1Pathology, Stanford University School of Medicine, Stanford, United States of America

2Pathology, Stanford University School of Medicine, Standford, United States of America

3Ophthalmology, Stanford University School of Medicine, Stanford, United States of America

4Departments of Otolaryngology and Neuroscience, University of California San Diego, La Jolla, United States of America

Find articles by Zhang, G. in: JCI | PubMed | Google Scholar

1Pathology, Stanford University School of Medicine, Stanford, United States of America

2Pathology, Stanford University School of Medicine, Standford, United States of America

3Ophthalmology, Stanford University School of Medicine, Stanford, United States of America

4Departments of Otolaryngology and Neuroscience, University of California San Diego, La Jolla, United States of America

Find articles by Ryan, A. in: JCI | PubMed | Google Scholar

1Pathology, Stanford University School of Medicine, Stanford, United States of America

2Pathology, Stanford University School of Medicine, Standford, United States of America

3Ophthalmology, Stanford University School of Medicine, Stanford, United States of America

4Departments of Otolaryngology and Neuroscience, University of California San Diego, La Jolla, United States of America

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Published November 21, 2024 - More info

J Clin Invest. https://doi.org/10.1172/JCI175562.
Copyright © 2024, Lee et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published November 21, 2024 - Version history
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Abstract

Activating transcription factor 6 (Atf6) is a key regulator of the unfolded protein response (UPR) and is important for endoplasmic reticulum (ER) function and protein homeostasis in metazoan cells. Patients carrying loss-of-function ATF6 disease alleles develop the cone dysfunction disorder, achromatopsia. The impact of loss of ATF6 function on other cell types, organs, and diseases in people remains unclear. Here, we reported 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 genders. In mice with hearing deficits, we found disorganized stereocilia on hair cells and focal loss of outer hair cells. Transcriptomic analysis of Atf6-/- cochleae revealed marked induction of UPR, especially through the PERK arm. These findings identify ATF6 as an essential regulator of cochlear health and function. Furthermore, they supported that ATF6 inactivation in people causes progressive sensorineural hearing loss as part of a blindness-deafness genetic syndrome targeting hair cells and cone photoreceptors. Lastly, our genetic findings support ER stress as an important pathomechanism underlying cochlear damage and hearing loss with clinical implications for patient lifestyle modifications that minimize environmental/physiologic sources of ER stress to the ear.

Supplemental material

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View Supplemental Table 1. List of medical genetic testing hearing loss genes.

View Supplemental Table 2. Differential expression (DESeq2) analysis (i.e., based on a cutoff for background value at 0.1 FPKM) from Atf6+/+ (n =5) and Atf6-/- (n=6) cochlea.

View Supplemental Table 3. Gene ontology (GO) analysis and Cytoscape visualization of differentially expressed genes identified by RNA-seq.* GO ID: http://geneontology.org

View Supplemental Table 4. List of UPR genes from RNA-seq analysis.

View Supplemental Table 5. List of ERAD genes from RNA-seq analysis.

View Supplemental Table 6. List of intrinsic apoptotic pathway response to ER stress genes from RNA-seq analysis.

View Supplemental Table 7. List of autophagy, lipid, oxidative stress, and phospholipid binding genes from RNA-seq analysis.

View Supplemental Table 8. List of actin filament and stereocilia-related genes from RNA-seq analysis.

View Supplemental Table 9. List of channel-related genes from RNA-seq analysis.

Version history
  • Version 1 (November 21, 2024): In-Press Preview
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