{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T14:51:50Z","timestamp":1790693510588,"version":"4.1.0"},"reference-count":57,"publisher":"Wiley","issue":"24","license":[{"start":{"date-parts":[[2021,12,1]],"date-time":"2021-12-01T00:00:00Z","timestamp":1638316800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2021,12]]},"abstract":"<jats:sec><jats:title>Abstract<\/jats:title><jats:p>DFNA25 is an autosomal\u2010dominant and progressive form of human deafness caused by mutations in the <jats:italic>SLC17A8<\/jats:italic> gene, which encodes the vesicular glutamate transporter type 3 (VGLUT3). To resolve the mechanisms underlying DFNA25, we studied phenotypes of mice harbouring the p.A221V mutation in humans (corresponding to p.A224V in mice). Using auditory brainstem response and distortion product otoacoustic emissions, we showed progressive hearing loss with intact cochlear amplification in the VGLUT3<jats:sup>A224V\/A224V<\/jats:sup> mouse. The summating potential was reduced, indicating the alteration of inner hair cell (IHC) receptor potential. Scanning electron microscopy examinations demonstrated the collapse of stereocilia bundles in IHCs, leaving those from outer hair cells unaffected. In addition, IHC ribbon synapses underwent structural and functional modifications at later stages. Using super\u2010resolution microscopy, we observed oversized synaptic ribbons and patch\u2010clamp membrane capacitance measurements showed an increase in the rate of the sustained releasable pool exocytosis. These results suggest that DFNA25 stems from a failure in the mechano\u2010transduction followed by a change in synaptic transfer. The VGLUT3<jats:sup>A224V\/A224V<\/jats:sup> mouse model opens the way to a deeper understanding and to a potential treatment for DFNA25.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key points<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>The vesicular glutamate transporter type 3 (VGLUT3) loads glutamate into the synaptic vesicles of auditory sensory cells, the inner hair cells (IHCs).<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>The VGLUT3\u2010p.A211V variant is associated with human deafness DFNA25.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Mutant mice carrying the VGLUT3\u2010p.A211V variant show progressive hearing loss.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>IHCs from mutant mice harbour distorted stereocilary bundles, which detect incoming sound stimulation, followed by oversized synaptic ribbons, which release glutamate onto the afferent nerve fibres.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>These results suggest that DFNA25 stems from the failure of auditory sensory cells to faithfully transduce acoustic cues into neural messages.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec>","DOI":"10.1113\/jp282181","type":"journal-article","created":{"date-parts":[[2021,11,16]],"date-time":"2021-11-16T03:14:25Z","timestamp":1637032465000},"page":"5397-5416","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["VGLUT3\u2010p.A211V variant fuses stereocilia bundles and elongates synaptic ribbons"],"prefix":"10.1113","volume":"599","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1638-8922","authenticated-orcid":false,"given":"Yuvraj","family":"Joshi","sequence":"first","affiliation":[{"name":"INM, Univ Montpellier, INSERM  Montpellier France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1910-0410","authenticated-orcid":false,"given":"Chlo\u00e9 P.","family":"Petit","sequence":"additional","affiliation":[{"name":"INM, Univ Montpellier, INSERM  Montpellier France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8000-1414","authenticated-orcid":false,"given":"St\u00e9phanie","family":"Miot","sequence":"additional","affiliation":[{"name":"INM, Univ Montpellier, INSERM  Montpellier France"},{"name":"Sorbonne Universit\u00e9s Universit\u00e9 Pierre et Marie Curie UM 119, Neurosciences Paris Seine \u2013 Institut de Biologie Paris Seine (NPS \u2013 IBPS)  Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie","family":"Guillet","sequence":"additional","affiliation":[{"name":"INM, Univ Montpellier, INSERM  Montpellier France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8341-1133","authenticated-orcid":false,"given":"Gaston","family":"Sendin","sequence":"additional","affiliation":[{"name":"INM, Univ Montpellier, INSERM  Montpellier France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5860-5772","authenticated-orcid":false,"given":"J\u00e9r\u00f4me","family":"Bourien","sequence":"additional","affiliation":[{"name":"INM, Univ Montpellier, INSERM  Montpellier France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2670-719X","authenticated-orcid":false,"given":"Jing","family":"Wang","sequence":"additional","affiliation":[{"name":"INM, Univ Montpellier, INSERM  Montpellier France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7837-7129","authenticated-orcid":false,"given":"R\u00e9my","family":"Pujol","sequence":"additional","affiliation":[{"name":"INM, Univ Montpellier, INSERM  Montpellier France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6253-0002","authenticated-orcid":false,"given":"Salah","family":"El Mestikawy","sequence":"additional","affiliation":[{"name":"Sorbonne Universit\u00e9s Universit\u00e9 Pierre et Marie Curie UM 119, Neurosciences Paris Seine \u2013 Institut de Biologie Paris Seine (NPS \u2013 IBPS)  Paris France"},{"name":"Department of Psychiatry Douglas Mental Health University Institute McGill University  Montreal Quebec Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3772-5190","authenticated-orcid":false,"given":"Jean\u2010Luc","family":"Puel","sequence":"additional","affiliation":[{"name":"INM, Univ Montpellier, INSERM  Montpellier France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0901-4666","authenticated-orcid":false,"given":"R\u00e9gis","family":"Nouvian","sequence":"additional","affiliation":[{"name":"INM, Univ Montpellier, INSERM  Montpellier France"},{"name":"INM, Univ Montpellier, INSERM, CNRS  Montpellier France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,12]]},"reference":[{"key":"e_1_2_5_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2012.05.019"},{"key":"e_1_2_5_3_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.30241"},{"key":"e_1_2_5_4_1","doi-asserted-by":"publisher","DOI":"10.1152\/jn.00738.2013"},{"key":"e_1_2_5_5_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1909675116"},{"key":"e_1_2_5_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrn2969"},{"key":"e_1_2_5_7_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0813213106"},{"key":"e_1_2_5_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2010.10.027"},{"key":"e_1_2_5_9_1","doi-asserted-by":"publisher","DOI":"10.15252\/embr.201847097"},{"key":"e_1_2_5_10_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.222546799"},{"key":"e_1_2_5_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/nn796"},{"key":"e_1_2_5_12_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.22-13-05442.2002"},{"key":"e_1_2_5_13_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1866-11.2011"},{"key":"e_1_2_5_14_1","doi-asserted-by":"publisher","DOI":"10.1086\/316925"},{"key":"e_1_2_5_15_1","doi-asserted-by":"publisher","DOI":"10.1113\/JP270818"},{"key":"e_1_2_5_16_1","doi-asserted-by":"publisher","DOI":"10.1152\/jn.00364.2006"},{"key":"e_1_2_5_17_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.29275"},{"key":"e_1_2_5_18_1","doi-asserted-by":"publisher","DOI":"10.1002\/cne.23345"},{"key":"e_1_2_5_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature06091"},{"key":"e_1_2_5_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature03418"},{"key":"e_1_2_5_21_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2228-18.2019"},{"key":"e_1_2_5_22_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.3389-10.2011"},{"key":"e_1_2_5_23_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00582306"},{"key":"e_1_2_5_24_1","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2019.00060"},{"key":"e_1_2_5_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2016.05.045"},{"key":"e_1_2_5_26_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.17-23-09133.1997"},{"key":"e_1_2_5_27_1","doi-asserted-by":"publisher","DOI":"10.15252\/embj.201592701"},{"key":"e_1_2_5_28_1","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1096-9861(19960722)371:2<208::AID-CNE2>3.0.CO;2-6"},{"key":"e_1_2_5_29_1","doi-asserted-by":"publisher","DOI":"10.1038\/nn.2293"},{"key":"e_1_2_5_30_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1812029116"},{"key":"e_1_2_5_31_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.97.2.883"},{"key":"e_1_2_5_32_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00026.2018"},{"key":"e_1_2_5_33_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-017-02612-y"},{"key":"e_1_2_5_34_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng1226"},{"key":"e_1_2_5_35_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.5230-07.2008"},{"key":"e_1_2_5_36_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1605737113"},{"key":"e_1_2_5_37_1","doi-asserted-by":"publisher","DOI":"10.15252\/embj.2020106010"},{"key":"e_1_2_5_38_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1416424112"},{"key":"e_1_2_5_39_1","doi-asserted-by":"publisher","DOI":"10.1038\/nn.2578"},{"key":"e_1_2_5_40_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnsyn.2021.678575"},{"key":"e_1_2_5_41_1","doi-asserted-by":"publisher","DOI":"10.1097\/WNR.0000000000001687"},{"key":"e_1_2_5_42_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0282-16.2017"},{"key":"e_1_2_5_43_1","first-page":"2690","article-title":"Stability of active zone components at the photoreceptor ribbon complex","volume":"16","author":"Regus\u2010Leidig H","year":"2010","journal-title":"Mol Vis"},{"key":"e_1_2_5_44_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2008.07.008"},{"key":"e_1_2_5_45_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0511005103"},{"key":"e_1_2_5_46_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12881-016-0269-3"},{"key":"e_1_2_5_47_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2005.06.004"},{"key":"e_1_2_5_48_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2011.01.031"},{"key":"e_1_2_5_49_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2007.11.032"},{"key":"e_1_2_5_50_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.3005-12.2012"},{"key":"e_1_2_5_51_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature02483"},{"key":"e_1_2_5_52_1","doi-asserted-by":"publisher","DOI":"10.1038\/nn.2870"},{"key":"e_1_2_5_53_1","doi-asserted-by":"publisher","DOI":"10.1523\/ENEURO.0295-16.2016"},{"key":"e_1_2_5_54_1","doi-asserted-by":"publisher","DOI":"10.1093\/embo-reports\/kvf159"},{"key":"e_1_2_5_55_1","doi-asserted-by":"publisher","DOI":"10.1001\/archotol.129.8.830"},{"key":"e_1_2_5_56_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0619-20.2021"},{"key":"e_1_2_5_57_1","doi-asserted-by":"publisher","DOI":"10.1002\/embj.201387110"},{"key":"e_1_2_5_58_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2010.11.013"}],"container-title":["The Journal of Physiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1113\/JP282181","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1113\/JP282181","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/pdf\/10.1113\/JP282181","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,24]],"date-time":"2023-08-24T02:34:21Z","timestamp":1692844461000},"score":1,"resource":{"primary":{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/10.1113\/JP282181"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,12]]},"references-count":57,"journal-issue":{"issue":"24","published-print":{"date-parts":[[2021,12]]}},"alternative-id":["10.1113\/JP282181"],"URL":"https:\/\/doi.org\/10.1113\/jp282181","archive":["Portico"],"relation":{},"ISSN":["0022-3751","1469-7793"],"issn-type":[{"value":"0022-3751","type":"print"},{"value":"1469-7793","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,12]]},"assertion":[{"value":"2021-08-20","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-11-01","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-12-01","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}