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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Veröffentlicht in:The Journal of clinical investigation Jg. 135; H. 3
Hauptverfasser: 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.
Format: Journal Article
Sprache:Englisch
Veröffentlicht: United States American Society for Clinical Investigation 01.02.2025
Schlagworte:
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
Online-Zugang:Volltext
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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.
AbstractList 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.
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. ATF6 inactivating patient mutations cause a blindness-deafness genetic syndrome characterized by cone photoreceptor dysfunction achromatopsia and sensorineural hearing loss.
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.sup.-/-] 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.sup.-/-] 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.
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.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.
Audience Academic
Author Kim, Kyle
Lee, Eun-Jin
Steinbergs, Korina J.
Ryan, Allen F.
Diaz-Aguilar, Monica Sophia
Zhang, Guirong
Safarta, Lance A.
Lin, Jonathan H.
Min, Hyejung
Chavez, Eduardo
AuthorAffiliation 4 Rush University Medical College, Chicago, Illinois, USA
2 Ophthalmology, Stanford University School of Medicine, Stanford, California, USA
3 VA Palo Alto Healthcare System, Palo Alto, California, USA
1 Departments of Pathology and
5 Departments of Otolaryngology and Neuroscience, UCSD and Veterans Administration Medical Center, La Jolla, California, USA
AuthorAffiliation_xml – name: 2 Ophthalmology, Stanford University School of Medicine, Stanford, California, USA
– name: 3 VA Palo Alto Healthcare System, Palo Alto, California, USA
– name: 5 Departments of Otolaryngology and Neuroscience, UCSD and Veterans Administration Medical Center, La Jolla, California, USA
– name: 1 Departments of Pathology and
– name: 4 Rush University Medical College, Chicago, Illinois, USA
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BackLink https://www.ncbi.nlm.nih.gov/pubmed/39570676$$D View this record in MEDLINE/PubMed
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CitedBy_id crossref_primary_10_1172_JCI188708
crossref_primary_10_1038_s41574_025_01129_5
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Issue 3
Keywords Genetics
Retinopathy
Ophthalmology
Molecular genetics
Genetic diseases
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Snippet 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...
Activating transcription factor 6 (Atf6) is a key regulator of the unfolded protein response (UPR) and is important for endoplasmic reticulum (ER) function and...
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SubjectTerms 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
Title Mutations in unfolded protein response regulator ATF6 cause hearing and vision loss syndrome
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https://pubmed.ncbi.nlm.nih.gov/PMC11785932
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