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

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 lo...

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Vydáno v:The Journal of clinical investigation Ročník 135; číslo 3
Hlavní autoři: Lee, Eun-Jin, Kim, Kyle, Diaz-Aguilar, Monica Sophia, Min, Hyejung, Chavez, Eduardo, Steinbergs, Korina J., Safarta, Lance A., Zhang, Guirong, Ryan, Allen F., Lin, Jonathan H.
Médium: Journal Article
Jazyk:angličtina
Vydáno: United States American Society for Clinical Investigation 01.02.2025
Témata:
Activating Transcription Factor 6 - genetics
Activating Transcription Factor 6 - metabolism
Animals
Blindness
Causes of
Color Vision Defects - genetics
Color Vision Defects - metabolism
Color Vision Defects - pathology
Deafness
Development and progression
eIF-2 Kinase - genetics
eIF-2 Kinase - metabolism
Endoplasmic Reticulum Stress - genetics
Female
Gene mutations
Genetic aspects
Genetics
Health aspects
Hearing loss
Hearing Loss, Sensorineural - genetics
Hearing Loss, Sensorineural - metabolism
Hearing Loss, Sensorineural - pathology
Humans
Male
Mice
Mice, Knockout
Mutation
Ophthalmology
Physiological aspects
Protein kinases
Proteins
Transcription factors
Type 2 diabetes
Unfolded Protein Response - genetics
United States
California
Genetics
Retinopathy
Ophthalmology
Molecular genetics
Genetic diseases
ISSN:1558-8238, 0021-9738, 1558-8238
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Shrnutí: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.
Bibliografie:ObjectType-Article-1
SourceType-Scholarly Journals-1
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content type line 23
ISSN:1558-8238
0021-9738
1558-8238
DOI:10.1172/JCI175562