{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T05:19:33Z","timestamp":1788153573101,"version":"build-2803163510"},"reference-count":28,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,8,29]],"date-time":"2026-08-29T00:00:00Z","timestamp":1787961600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100019871","name":"Beijing Obstetrics and Gynecology Hospital, Capital Medical University","doi-asserted-by":"crossref","award":["FCYYJC202406"],"award-info":[{"award-number":["FCYYJC202406"]}],"id":[{"id":"10.13039\/501100019871","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100019871","name":"Beijing Obstetrics and Gynecology Hospital, Capital Medical University","doi-asserted-by":"crossref","award":["FCYY202011"],"award-info":[{"award-number":["FCYY202011"]}],"id":[{"id":"10.13039\/501100019871","id-type":"DOI","asserted-by":"crossref"}]},{"award":["FCYYJC202406"],"award-info":[{"award-number":["FCYYJC202406"]}],"id":[{"id":"https:\/\/ror.org\/013xs5b60","id-type":"ROR","asserted-by":"publisher"}]},{"award":["FCYY202011"],"award-info":[{"award-number":["FCYY202011"]}],"id":[{"id":"https:\/\/ror.org\/013xs5b60","id-type":"ROR","asserted-by":"publisher"}]},{"name":"High Innovation Plan","award":["G202522148"],"award-info":[{"award-number":["G202522148"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background\/Objectives: M\u00fcllerian duct anomalies (MDAs) are congenital structural abnormalities of the female reproductive tract with heterogeneous and incompletely defined genetic contributions. PAX8 is a developmental transcription factor implicated in thyroid and urogenital development. This study assessed the functional consequences of a rare PAX8 variant identified by whole-exome sequencing (WES) in an MDA cohort, without presuming a causal relationship. Methods: WES was performed in 150 patients with MDAs. The PAX8 c.791T&gt;C (p.Leu264Pro) variant was evaluated using computational predictions, cellular assays, and RNA sequencing in a 293FT transient-overexpression model. Results: The heterozygous p.Leu264Pro variant was identified in one patient with a complex septate uterine, cervical, and vaginal anomaly and was absent from 120 controls. Parental samples were unavailable. No statistically significant difference in construct-derived PAX8 mRNA abundance was detected between PAX8-WT and PAX8-L264P, and both proteins showed predominantly nuclear localization. In the direct PAX8-WT-versus-L264P RNA-seq comparison, 76 transcripts had nominal p values below 0.05, but none remained significant after Benjamini\u2013Hochberg correction, and no gene met the prespecified differential-expression criteria. AK5, RCBTB2, and IFT88 were identified as candidate PAX8-responsive genes in this experimental system. Conclusions: No major functional difference was detected between PAX8-WT and L264P under the tested conditions; however, these findings do not establish functional equivalence or exclude smaller, tissue-specific, or developmental-stage-specific effects. The p.Leu264Pro variant remains a variant of uncertain significance with respect to MDAs, and the functional results were not used as benign evidence under ACMG\/AMP criterion BS3.<\/jats:p>","DOI":"10.3390\/genes17091039","type":"journal-article","created":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T02:08:58Z","timestamp":1788142138000},"page":"1039","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Functional Characterization of the PAX8 p.Leu264Pro Variant Identified in a Patient with a M\u00fcllerian Duct Anomaly"],"prefix":"10.3390","volume":"17","author":[{"given":"Lin","family":"He","sequence":"first","affiliation":[{"name":"Central Laboratory, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing Maternal and Child Health Care Hospital, Dongcheng, Beijing 100006, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"software","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"given":"Liangzhe","family":"Li","sequence":"additional","affiliation":[{"name":"Central Laboratory, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing Maternal and Child Health Care Hospital, Dongcheng, Beijing 100006, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"software","vocabulary":"credit"}]},{"given":"Yuxiao","family":"Li","sequence":"additional","affiliation":[{"name":"Central Laboratory, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing Maternal and Child Health Care Hospital, Dongcheng, Beijing 100006, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"}]},{"given":"Yujun","family":"Sun","sequence":"additional","affiliation":[{"name":"Central Laboratory, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing Maternal and Child Health Care Hospital, Dongcheng, Beijing 100006, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"data-curation","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"}]},{"given":"Zhi","family":"Zheng","sequence":"additional","affiliation":[{"name":"Central Laboratory, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing Maternal and Child Health Care Hospital, Dongcheng, Beijing 100006, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"}]},{"given":"Chunfang","family":"Chu","sequence":"additional","affiliation":[{"name":"Department of Gynecology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing Maternal and Child Health Care Hospital, Chaoyang, Beijing 100026, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"resources","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"conceptualization","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3597-3350","authenticated-orcid":false,"given":"Lin","family":"Li","sequence":"additional","affiliation":[{"name":"Central Laboratory, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing Maternal and Child Health Care Hospital, Dongcheng, Beijing 100006, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"supervision","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"conceptualization","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1093\/humupd\/dmn018","article-title":"Prevalence and diagnosis of congenital uterine anomalies in women with reproductive failure: A critical appraisal","volume":"14","author":"Saravelos","year":"2008","journal-title":"Hum. 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