Novel mutations in the TP63 gene are potentially associated with Müllerian duct anomalies.

<bold>Study Question: </bold>Are mutations and/or polymorphisms in the TP63 gene associated with human Müllerian duct anomalies (MDAs)?<bold>Summary Answer: </bold>The novel mutation c.*374 G > A in the TP63 gene resulted in decreased expression of TP63 by generating new binding sites with miR-1260a/miR-532-3p and revealed the potential association between TP63 and human MDAs.<bold>What Is Known Already: </bold>It has been shown that mice lacking Tp63 exhibit hypoplastic genitalia, a single cloacal opening, and persistence of columnar epithelium at lower genital tract sites. It has also been reported that a nonsense mutation in EMX2 results in decreased TP63 expression in a woman with MDAs. However, generally in humans the association between TP63 and MDAs is unknown.<bold>Study Design, Size, Duration: </bold>A total of 200 unrelated Chinese women with MDAs and 200 unrelated Chinese women with a normal uterus and vagina, as controls, were recruited in the Center for Reproductive Medicine of Shandong University. All participants had a normal karyotype (46, XX).<bold>Participants/materials, Setting, Methods: </bold>The 20 exons of the TP63 gene were sequenced in 200 cases and 200 controls. Putative binding sites for microRNAs were validated by dual luciferase activity assays. The role of microRNAs was further examined by western blot.<bold>Main Results and the Role Of Chance: </bold>Sequence analysis revealed 15 known single-nucleotide polymorphisms. Additionally, three novel heterozygous variants, c.387 G > C, c.*374 G > A and c.*749 G > A, were identified in three patients with MDAs, none of which were detected in controls. Variant c.*374 G > A, located in the 3' untranslated region, was highly conserved among mammals and predicted to create microRNAs binding sites, which was confirmed by dual luciferase activity assays. Western blot demonstrated that the binding with miR-1260a/miR-532-3p resulting from the variation c.*374 G > A decreased the expression of TP63.<bold>Large Scale Data: </bold>N/A LIMITATIONS, REASONS FOR CAUTION: Further study is needed to uncover the role of the EMX2-TP63 pathway in the development of the Müllerian duct.<bold>Wider Implications Of the Findings: </bold>This study revealed the possible association between TP63 and MDAs and suggested a potential contribution of microRNA-regulated expression of genes in the etiology of MDAs.<bold>Study Funding/competing Interests: </bold>This research was supported by National Basic Research Program of China (973 Program) (2012CB944700), the State Key Program of National Natural Science Foundation of China (81430029), the National Natural Science Foundation of China (81270662, 81471509), China Postdoctoral Science Foundation (2014M561939) and the Scientific Research Foundation of Shandong Province of Outstanding Young Scientists (BS2014YY013, 2014BSE27022). The authors have no competing interests. [ABSTRACT FROM AUTHOR]