{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:21:51Z","timestamp":1787026911599,"version":"build-2736575974"},"reference-count":42,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,9,29]],"date-time":"2022-09-29T00:00:00Z","timestamp":1664409600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100011852","name":"Paracelsus Medizinische Privatuniversit\u00e4t","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100011852","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Mol. Neurosci."],"abstract":"<jats:p>\n                    Hearing loss (HL) is the most common sensory defect and affects 450 million people worldwide in a disabling form. Pathogenic sequence alterations in the\n                    <jats:italic>POU3F4<\/jats:italic>\n                    gene, which encodes a transcription factor, are causative of the most common type of X-linked deafness (X-linked deafness type 3, DFN3, DFNX2). POU3F4-related deafness is characterized by a typical inner ear malformation, namely an incomplete partition of the cochlea type 3 (IP3), with or without an enlargement of the vestibular aqueduct (EVA). The pathomechanism underlying POU3F4-related deafness and the corresponding transcriptional targets are largely uncharacterized. Two male patients belonging to a Caucasian cohort with HL and EVA who presented with an IP3 were submitted to genetic analysis. Two novel sequence variants in\n                    <jats:italic>POU3F4<\/jats:italic>\n                    were identified by Sanger sequencing. In cell-based assays, the corresponding protein variants (p.S74Afs*8 and p.C327*) showed an aberrant expression and subcellular distribution and lack of transcriptional activity. These two protein variants failed to upregulate the transcript levels of the amino acid transporter gene\n                    <jats:italic>SLC6A20<\/jats:italic>\n                    , which was identified as a novel transcriptional target of POU3F4 by RNA sequencing and RT-qPCR. Accordingly,\n                    <jats:italic>POU3F4<\/jats:italic>\n                    silencing by siRNA resulted in downregulation of\n                    <jats:italic>SLC6A20<\/jats:italic>\n                    in mouse embryonic fibroblasts. Moreover, we showed for the first time that SLC6A20 is expressed in the mouse cochlea, and co-localized with POU3F4 in the spiral ligament. The findings presented here point to a novel role of amino acid transporters in the inner ear and pave the way for mechanistic studies of POU3F4-related HL.\n                  <\/jats:p>","DOI":"10.3389\/fnmol.2022.999833","type":"journal-article","created":{"date-parts":[[2022,9,29]],"date-time":"2022-09-29T11:10:01Z","timestamp":1664449801000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":11,"title":["Novel POU3F4 variants identified in patients with inner ear malformations exhibit aberrant cellular distribution and lack of SLC6A20 transcriptional upregulation"],"prefix":"10.3389","volume":"15","author":[{"given":"Emanuele","family":"Bernardinelli","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebastian","family":"Roesch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edi","family":"Simoni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela","family":"Marino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerd","family":"Rasp","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Astolfi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Sarikas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Dossena","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,9,29]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"733","DOI":"10.1002\/cyto.a.20896","article-title":"Quantifying colocalization by correlation: The pearson correlation coefficient is superior to the mander\u2019s overlap coefficient.","volume":"77","author":"Adler","year":"2010","journal-title":"Cytometry A"},{"key":"B2","doi-asserted-by":"publisher","first-page":"3881","DOI":"10.1172\/JCI36625","article-title":"Iminoglycinuria and hyperglycinuria are discrete human phenotypes resulting from complex mutations in proline and glycine transporters.","volume":"118","author":"Broer","year":"2008","journal-title":"J. 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