{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T03:15:01Z","timestamp":1791947701691,"version":"4.3.4"},"reference-count":78,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"738","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Sci. Signal."],"published-print":{"date-parts":[[2022,6,14]]},"abstract":"<jats:p>\n            Resistance to thyroid hormone due to mutations in\n            <jats:italic>THRA<\/jats:italic>\n            , which encodes the thyroid hormone receptor \u03b1 (TR\u03b11), shows variable clinical presentation. Mutations affecting TR\u03b21 and TR\u03b22 cause deafness in mice and have been associated with deafness in humans. To test whether TR\u03b11 also affects hearing function, we used mice heterozygous for a frameshift mutation in\n            <jats:italic>Thra<\/jats:italic>\n            that is similar to human\n            <jats:italic>THRA<\/jats:italic>\n            mutations (\n            <jats:italic>\n              Thra\n              <jats:sup>\n                S1\/\n                <jats:bold>+<\/jats:bold>\n              <\/jats:sup>\n            <\/jats:italic>\n            mice) and reduces tissue sensitivity to thyroid hormone. Compared to wild-type littermates,\n            <jats:italic>\n              Thra\n              <jats:sup>S1\/+<\/jats:sup>\n            <\/jats:italic>\n            mice showed moderate high-frequency sensorineural hearing loss as juveniles and increased age-related hearing loss. Ultrastructural examination revealed aberrant orientation of ~20% of sensory outer hair cells (OHCs), as well as increased numbers of mitochondria with fragmented morphology and autophagic vacuoles in both OHCs and auditory nerve fibers. Molecular dissection of the OHC lateral wall components revealed that the potassium ion channel Kcnq4 was aberrantly targeted to the cytoplasm of mutant OHCs. In addition, mutant cochleae showed increased oxidative stress, autophagy, and mitophagy associated with greater age-related cochlear cell damage, demonstrating that TR\u03b11 is required for proper development of OHCs and for maintenance of OHC function. These findings suggest that patients with\n            <jats:italic>THRA<\/jats:italic>\n            mutations may present underdiagnosed, mild hearing loss and may be more susceptible to age-related hearing loss.\n          <\/jats:p>","DOI":"10.1126\/scisignal.abj4583","type":"journal-article","created":{"date-parts":[[2022,6,14]],"date-time":"2022-06-14T17:55:26Z","timestamp":1655229326000},"source":"Crossref","is-referenced-by-count":15,"title":["A disease-associated mutation in thyroid hormone receptor \u03b11 causes hearing loss and sensory hair cell patterning defects in mice"],"prefix":"10.1126","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3109-4575","authenticated-orcid":true,"given":"Corentin","family":"Affortit","sequence":"first","affiliation":[{"name":"Institute for Neurosciences of Montpellier (INM), University Montpellier, INSERM, Montpellier, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5843-7086","authenticated-orcid":true,"given":"Fabian","family":"Blanc","sequence":"additional","affiliation":[{"name":"Institute for Neurosciences of Montpellier (INM), University Montpellier, INSERM, Montpellier, France."},{"name":"Department of ENT and Head and Neck Surgery, University Hospital of Montpellier, Montpellier, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jamal","family":"Nasr","sequence":"additional","affiliation":[{"name":"Institute for Neurosciences of Montpellier (INM), University Montpellier, INSERM, Montpellier, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3342-8727","authenticated-orcid":true,"given":"Jean-Charles","family":"Ceccato","sequence":"additional","affiliation":[{"name":"Institute for Neurosciences of Montpellier (INM), University Montpellier, INSERM, Montpellier, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3545-569X","authenticated-orcid":true,"given":"Suzy","family":"Markossian","sequence":"additional","affiliation":[{"name":"Institut de G\u00e9nomique Fonctionnelle de Lyon (IGFL), INRAE USC1370, CNRS (UMR5242), ENS, Lyon, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0029-6222","authenticated-orcid":true,"given":"Romain","family":"Guyot","sequence":"additional","affiliation":[{"name":"Institut de G\u00e9nomique Fonctionnelle de Lyon (IGFL), INRAE USC1370, CNRS (UMR5242), ENS, Lyon, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3772-5190","authenticated-orcid":true,"given":"Jean-Luc","family":"Puel","sequence":"additional","affiliation":[{"name":"Institute for Neurosciences of Montpellier (INM), University Montpellier, INSERM, Montpellier, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3360-2345","authenticated-orcid":true,"given":"Fr\u00e9d\u00e9ric","family":"Flamant","sequence":"additional","affiliation":[{"name":"Institut de G\u00e9nomique Fonctionnelle de Lyon (IGFL), INRAE USC1370, CNRS (UMR5242), ENS, Lyon, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2670-719X","authenticated-orcid":true,"given":"Jing","family":"Wang","sequence":"additional","affiliation":[{"name":"Institute for Neurosciences of Montpellier (INM), University Montpellier, INSERM, Montpellier, France."},{"name":"Department of ENT and Head and Neck Surgery, University Hospital of Montpellier, Montpellier, France."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrendo.2013.58"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00030.2013"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1096\/fj.11-195933"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.2004911"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.19.12.7913"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.mce.2017.01.054"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0378-5955(97)00014-2"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1097-4695(19990215)38:3<338::AID-NEU4>3.0.CO;2-1"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1210\/en.2011-1834"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.91.2.439"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1210626110"},{"key":"e_1_3_3_13_2","first-page":"2768","article-title":"Prevalence and mechanisms of hearing loss in patients with resistance to thyroid hormone","volume":"81","author":"Brucker-Davis F.","year":"1996","unstructured":"F. 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