{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T17:54:01Z","timestamp":1775066041710,"version":"3.50.1"},"reference-count":60,"publisher":"S. Karger AG","issue":"1-6","license":[{"start":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T00:00:00Z","timestamp":1772064000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/karger.com\/pages\/terms-and-conditions"},{"start":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T00:00:00Z","timestamp":1772064000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/karger.com\/pages\/terms-and-conditions"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Sex Dev"],"abstract":"<jats:p>Introduction: The pre-B-cell leukemia transcription factor encoded by PBX1 is expressed throughout human embryonic stages. Accumulating cases with differences of sex development (DSDs) have been reported harboring PBX1 variants, suggesting a yet elusive role of PBX1 in the gonadal differentiation and sexual development processes. Methods: We report a syndromic case of 46,XY DSD presenting severely undervirilized genitalia and gonadal dysgenesis with mixed ovarian and testicular differentiation, where whole-exome sequencing analysis identified a novel missense variant c.710G&gt;C (p.R237T) in the highly conserved nuclear localization sequence in the three-amino acid loop extension domain of PBX1. Results: Compared with wild-type (WT) PBX1, PBX1 p.R237T reduced protein stability and hampered nuclear translocation of PBX1 in the inducible Flp-In TREx HEK293 cells. Induction with tetracycline significantly decreased cell proliferation in both Flp-In HEK293 PBX1 WT and p.R237T cells compared to untransfected HEK293 cells, while adhesive ability was not different. RNA sequencing identified differentially expressed genes in DSD-related genes, including MAP3K4, EMX2, KISS1R, and HOXA13 in cells expressing PBX1 p.R237T when compared to cells expressing WT PBX1. Conclusion: Altogether, our results demonstrated the deleterious functional consequences of the rare PBX1 p.R237T variant identified in a Taiwanese proband with 46,XY DSD.<\/jats:p>","DOI":"10.1159\/000550575","type":"journal-article","created":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T17:00:55Z","timestamp":1772125255000},"page":"45-57","source":"Crossref","is-referenced-by-count":0,"title":["Functional Validation of a Novel PBX1 Missense Variant in a 46,XY 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