{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T20:33:33Z","timestamp":1792787613772,"version":"4.5.0"},"reference-count":116,"publisher":"American Society for Clinical Investigation","issue":"3","license":[{"start":{"date-parts":[[2025,2,3]],"date-time":"2025-02-03T00:00:00Z","timestamp":1738540800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"VA","award":["I01BX002284 I01BX001205"],"award-info":[{"award-number":["I01BX002284 I01BX001205"]}]},{"name":"NIH","award":["P30EY026877,R01EY027735,R01AG046495,R01NS125674,R01NS088485"],"award-info":[{"award-number":["P30EY026877,R01EY027735,R01AG046495,R01NS125674,R01NS088485"]}]},{"name":"CIRM","award":["DISC2-10973"],"award-info":[{"award-number":["DISC2-10973"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,2,3]]},"abstract":"<jats:p>\n                    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\n                    <jats:italic>ATF6<\/jats:italic>\n                    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\n                    <jats:italic>ATF6<\/jats:italic>\n                    disease alleles and that\n                    <jats:italic>\n                      Atf6\n                      <jats:sup>\u2013\/\u2013<\/jats:sup>\n                    <\/jats:italic>\n                    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\n                    <jats:italic>\n                      Atf6\n                      <jats:sup>\u2013\/\u2013<\/jats:sup>\n                    <\/jats:italic>\n                    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.\n                  <\/jats:p>","DOI":"10.1172\/jci175562","type":"journal-article","created":{"date-parts":[[2024,11,21]],"date-time":"2024-11-21T12:00:27Z","timestamp":1732190427000},"source":"Crossref","is-referenced-by-count":18,"title":["Mutations in unfolded protein response regulator ATF6 cause hearing and vision loss syndrome"],"prefix":"10.1172","volume":"135","author":[{"given":"Eun-Jin","family":"Lee","sequence":"first","affiliation":[{"name":"Departments of Pathology and"},{"name":"Ophthalmology, Stanford University School of Medicine, Stanford, California, USA."},{"name":"VA Palo Alto Healthcare System, Palo Alto, California, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyle","family":"Kim","sequence":"additional","affiliation":[{"name":"Departments of Pathology and"},{"name":"VA Palo Alto Healthcare System, Palo Alto, California, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monica Sophia","family":"Diaz-Aguilar","sequence":"additional","affiliation":[{"name":"Departments of Pathology and"},{"name":"Ophthalmology, Stanford University School of Medicine, Stanford, California, USA."},{"name":"VA Palo Alto Healthcare System, Palo Alto, California, USA."},{"name":"Rush University Medical College, Chicago, Illinois, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyejung","family":"Min","sequence":"additional","affiliation":[{"name":"Departments of Pathology and"},{"name":"Ophthalmology, Stanford University School of Medicine, Stanford, California, USA."},{"name":"VA Palo Alto Healthcare System, Palo Alto, California, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eduardo","family":"Chavez","sequence":"additional","affiliation":[{"name":"Departments of Otolaryngology and Neuroscience, UCSD and Veterans Administration Medical Center, La Jolla, California, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Korina J.","family":"Steinbergs","sequence":"additional","affiliation":[{"name":"Departments of Pathology and"},{"name":"Ophthalmology, Stanford University School of Medicine, Stanford, California, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lance A.","family":"Safarta","sequence":"additional","affiliation":[{"name":"Departments of Pathology and"},{"name":"Ophthalmology, Stanford University School of Medicine, Stanford, California, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guirong","family":"Zhang","sequence":"additional","affiliation":[{"name":"Departments of Pathology and"},{"name":"VA Palo Alto Healthcare System, Palo Alto, California, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Allen F.","family":"Ryan","sequence":"additional","affiliation":[{"name":"Departments of Otolaryngology and Neuroscience, UCSD and Veterans Administration Medical Center, La Jolla, California, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7438-6941","authenticated-orcid":true,"given":"Jonathan H.","family":"Lin","sequence":"additional","affiliation":[{"name":"Departments of Pathology and"},{"name":"Ophthalmology, Stanford University School of Medicine, Stanford, California, USA."},{"name":"VA Palo Alto Healthcare System, Palo Alto, California, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"232","published-online":{"date-parts":[[2025,2,3]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.10.11.3787"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1209038"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1247\/csf.06024"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/S1097-2765(00)00133-7"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.25.3.921-932.2005"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(19)61473-0"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2007.07.005"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2007.07.018"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1038\/nature17041"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3319"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1606387114"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1038\/ejhg.2017.131"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.136041"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.aan5785"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2103196118"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1007\/s00439-015-1571-4"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.15-16778"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.19-27047"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-021-95895-7"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.e09-02-0133"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1016\/j.metabol.2012.01.004"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1004335"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.116.310266"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-08129-2"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1111\/jnc.12981"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2011.01.003"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1007\/s11010-011-1211-9"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M110.156430"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuint.2015.12.009"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1210\/en.2014-1522"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1111\/jnc.13714"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1186\/s13075-019-1988-6"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1288\/00005537-197901000-00001"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.3109\/00206098009070071"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1007\/s101620010075"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2008.07.016"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1016\/j.heares.2011.11.007"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1016\/0091-6749(88)90168-6"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1001\/archotol.125.1.12"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1017\/S0022215118001275"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1186\/s12913-018-3139-1"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2021.815627"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0036226"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1186\/s13643-019-1073-x"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijporl.2016.03.032"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2008.02.028"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1016\/j.heares.2014.01.007"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1002\/cphy.c160049"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1016\/j.heares.2017.01.003"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1016\/j.tins.2018.12.006"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1016\/j.heares.2008.08.010"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.6274-11.2012"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1709-12.2012"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1016\/j.tins.2019.03.006"},{"issue":"107","key":"B55","doi-asserted-by":"crossref","DOI":"10.3791\/53561","article-title":"Whole mount dissection and immunofluorescence of the adult mouse cochlea","author":"Montgomery","year":"2016","journal-title":"J Vis Exp"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.92.21.9815"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1002\/cm.20080"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2020.108431"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.1007\/BF01774064"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkz369"},{"key":"B61","doi-asserted-by":"publisher","DOI":"10.1038\/75556"},{"key":"B62","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2007.324"},{"key":"B63","doi-asserted-by":"publisher","DOI":"10.1038\/ncb0805-766"},{"key":"B64","doi-asserted-by":"publisher","DOI":"10.1038\/nrm3440"},{"key":"B65","doi-asserted-by":"publisher","DOI":"10.1126\/science.aan5835"},{"key":"B66","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcdb.2018.09.013"},{"key":"B67","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajpath.2022.12.002"},{"key":"B68","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.045625"},{"key":"B69","doi-asserted-by":"publisher","DOI":"10.1038\/ncb2738"},{"key":"B70","doi-asserted-by":"publisher","DOI":"10.1016\/S1097-2765(03)00105-9"},{"key":"B71","doi-asserted-by":"publisher","DOI":"10.1038\/sj.emboj.7600030"},{"key":"B72","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.23.21.7448-7459.2003"},{"key":"B73","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M609490200"},{"key":"B74","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2004.06.010"},{"key":"B75","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2013.03.024"},{"key":"B76","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M304490200"},{"key":"B77","doi-asserted-by":"publisher","DOI":"10.1126\/science.1146361"},{"key":"B78","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamcr.2013.06.028"},{"key":"B79","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.75.2.339"},{"key":"B80","doi-asserted-by":"publisher","DOI":"10.3389\/fnmol.2019.00332"},{"key":"B81","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2022.110665"},{"key":"B82","doi-asserted-by":"publisher","DOI":"10.1121\/1.382104"},{"key":"B83","doi-asserted-by":"publisher","DOI":"10.1121\/1.4840775"},{"key":"B84","doi-asserted-by":"publisher","DOI":"10.1016\/j.joto.2021.11.004"},{"key":"B85","doi-asserted-by":"publisher","DOI":"10.1016\/j.heares.2010.03.007"},{"key":"B86","doi-asserted-by":"publisher","DOI":"10.1007\/s10162-016-0596-2"},{"key":"B87","doi-asserted-by":"publisher","DOI":"10.1038\/cddis.2016.386"},{"key":"B88","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-020-2286-6"},{"key":"B89","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2006.02.021"},{"key":"B90","doi-asserted-by":"publisher","DOI":"10.26508\/lsa.202101068"},{"key":"B91","doi-asserted-by":"publisher","DOI":"10.1254\/jphs.11227FP"},{"key":"B92","doi-asserted-by":"publisher","DOI":"10.1038\/cddis.2015.108"},{"key":"B93","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-02960-1"},{"key":"B94","doi-asserted-by":"publisher","DOI":"10.4103\/1463-1741.192481"},{"key":"B95","doi-asserted-by":"publisher","DOI":"10.1042\/BSR20181749"},{"key":"B96","doi-asserted-by":"publisher","DOI":"10.1016\/j.exger.2015.07.003"},{"key":"B97","doi-asserted-by":"publisher","DOI":"10.2337\/db20-1174"},{"key":"B98","doi-asserted-by":"publisher","DOI":"10.1186\/s13023-018-0852-0"},{"key":"B99","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-023-05912-y"},{"key":"B100","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/7.13.2021"},{"key":"B101","doi-asserted-by":"publisher","DOI":"10.1038\/2441"},{"key":"B102","doi-asserted-by":"publisher","DOI":"10.1172\/JCI97498"},{"key":"B103","doi-asserted-by":"publisher","DOI":"10.1016\/j.visres.2007.08.015"},{"key":"B104","unstructured":"World Health Organization. Deafness and hearing loss. https:\/\/www.who.int\/news-room\/fact-sheets\/detail\/deafness-and-hearing-loss Updated February 2, 2024. Accessed January 17, 2025"},{"key":"B105","doi-asserted-by":"publisher","DOI":"10.1007\/s13238-010-0118-7"},{"key":"B106","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2015.12.050"},{"key":"B107","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-020-75058-w"},{"key":"B108","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.37168"},{"key":"B109","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.15550"},{"issue":"1\u20132","key":"B110","first-page":"71","article-title":"Differential actions of isoflurane and ketamine-based anaesthetics on cochlear function in the mouse","volume":"292","author":"Cederholm","year":"2012","journal-title":"Hear Res"},{"key":"B111","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2105-12-323"},{"key":"B112","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-014-0550-8"},{"key":"B113","doi-asserted-by":"publisher","DOI":"10.1038\/s41596-018-0103-9"},{"key":"B114","doi-asserted-by":"publisher","DOI":"10.1101\/gr.1239303"},{"key":"B115","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btr260"},{"key":"B116","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0506580102"}],"container-title":["Journal of Clinical Investigation"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.jci.org\/articles\/view\/175562\/files\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T22:49:32Z","timestamp":1779230972000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.jci.org\/articles\/view\/175562"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,2,3]]},"references-count":116,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2024,12,2]]},"published-print":{"date-parts":[[2025,2,3]]}},"alternative-id":["10.1172\/JCI175562"],"URL":"https:\/\/doi.org\/10.1172\/jci175562","relation":{},"ISSN":["1558-8238"],"issn-type":[{"value":"1558-8238","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,2,3]]},"article-number":"e175562"}}