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Although recent studies on the other USH genes, <jats:italic>PDZD7<\/jats:italic> and <jats:italic>Ush1 g<\/jats:italic>, showed a possibility of haploinsufficiency effect, the potential contribution of heterozygous <jats:italic>Whrn<\/jats:italic> loss to hearing loss remains unclear.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods<\/jats:title>\n            <jats:p>To investigate the effect of <jats:italic>Whrn<\/jats:italic> haploinsufficiency, we conducted a longitudinal study assessing auditory function in heterozygous <jats:italic>Whrn<\/jats:italic> mutant (<jats:italic>Whrn<\/jats:italic>\n              <jats:sup>+<jats:italic>\/\u2212<\/jats:italic>\n              <\/jats:sup>) mice in which long isoform of <jats:italic>Whrn<\/jats:italic> was deleted by replacing exon 1 with Neo cassette without disturbing short isoform. The threshold of auditory brainstem responses (ABRs) was measured on 135 <jats:italic>Whrn<\/jats:italic>\n              <jats:sup>+\/<jats:italic>\u2212<\/jats:italic>\n              <\/jats:sup> mice and littermate 133 wild-type (WT) mice from 1 to 6\u00a0months of ages. From those data, the threshold from male and female were separately analyzed to investigate sex-dependent effect. To further investigate underlie mechanisms, hair cell death was investigated using immunohistostaining from 4 to 5 WT, 5 female <jats:italic>Whrn<\/jats:italic>\n              <jats:sup>+<jats:italic>\/\u2212<\/jats:italic>\n              <\/jats:sup>, and 7 male <jats:italic>Whrn<\/jats:italic>\n              <jats:sup>+<jats:italic>\/\u2212<\/jats:italic>\n              <\/jats:sup> mice at 4\u20135\u00a0months old.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>Hearing threshold was significantly increased with aging in <jats:italic>Whrn<\/jats:italic>\n              <jats:sup>+<jats:italic>\/\u2013<\/jats:italic>\n              <\/jats:sup> mice compared to WT controls. Both WT and <jats:italic>Whrn<\/jats:italic>\n              <jats:sup>+<jats:italic>\/\u2013<\/jats:italic>\n              <\/jats:sup> mice exhibited sex-dependent variations in hearing sensitivity. Notably, <jats:italic>Whrn<\/jats:italic>\n              <jats:sup>+<jats:italic>\/\u2013<\/jats:italic>\n              <\/jats:sup> males showed a progressive hearing loss with age, while <jats:italic>Whrn<\/jats:italic>\n              <jats:sup>+<jats:italic>\/\u2013<\/jats:italic>\n              <\/jats:sup> females exhibited elevated hearing thresholds as early as 1\u20132\u00a0month of age compared to WT females.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusion<\/jats:title>\n            <jats:p>These results provide evidence for a haploinsufficiency effect of <jats:italic>Whrn<\/jats:italic> on auditory function and highlight its potential role in progressive sensorineural hearing loss.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1007\/s10162-025-00991-4","type":"journal-article","created":{"date-parts":[[2025,5,13]],"date-time":"2025-05-13T16:30:42Z","timestamp":1747153842000},"page":"239-247","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Haploinsufficiency of Whrn Contributes to Progressive Sensorineural Hearing Loss in C57BL6 Mice"],"prefix":"10.1007","volume":"26","author":[{"given":"Han-Gyu","family":"Bae","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sean","family":"Kashiwagura","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrew","family":"Jung","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elizabeth","family":"Gould","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0207-8410","authenticated-orcid":false,"given":"Jun Hee","family":"Kim","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,5,13]]},"reference":[{"key":"991_CR1","doi-asserted-by":"publisher","first-page":"512","DOI":"10.1097\/GIM.0b013e3181e5afb8","volume":"12","author":"WJ Kimberling","year":"2010","unstructured":"Kimberling WJ, Hildebrand MS, Shearer AE, Jensen ML, Halder JA, Trzupek K et al (2010) Frequency of Usher syndrome in two pediatric populations: implications for genetic screening of deaf and hard of hearing children. 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