title: A novel functional variant in Wilms' Tumor 1 (WT1) is associated with idiopathic non-obstructive azoospermia.
abstract: Idiopathic nonobstructive azoospermia (INOA) is one of the most severe forms of male infertility, yet its pathophysiology remains unclear. WT1 (Wilms' tumor 1) regulates the polarity of Sertoli cells, thereby playing a critical, indirect role in spermatogenesis. Here, we evaluated WT1 gene variation associates with INOA by assessing its promoter and coding regions in 200 patients diagnosed with INOA and 200 proven-fertile men. Three novel variants in the WT1 coding region were detected only in INOA patients, including two synonymous variants and one missense variant, p.Phe435Leu (p.F435L), which was predicted to be deleterious to protein function. The results of dual luciferase reporter showed that the WT1 p.F435L variant decreases transcription of COL4A1 and WNT4 promoters through a dominant-negative effect. Furthermore, chromatin immunoprecipitation assays revealed that COL4A1 and WNT4 promoter is directly bound by wild-type WT1 protein, but not the p.F435L WT1 variant. Thus, we identified a novel functional variant of WT1 functionally associated with INOA. Mol. Reprod. Dev. 84: 222-228, 2017. © 2017 Wiley Periodicals, Inc.
authors.affiliation: Reproductive Medical Center, The Henan Province People's Hospital, Zhengzhou, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Xu
authors.affiliation: Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
authors.forename: Lile
authors.initials: L
authors.lastname: Jiang
authors.affiliation: Reproductive Medical Center, The Henan Province People's Hospital, Zhengzhou, China.
authors.forename: Wenzhu
authors.initials: W
authors.lastname: Yu
authors.affiliation: Reproductive Medical Center, The Henan Province People's Hospital, Zhengzhou, China.
authors.forename: Haibin
authors.initials: H
authors.lastname: Guo
authors.affiliation: Reproductive Medical Center, The Henan Province People's Hospital, Zhengzhou, China.
authors.forename: Helong
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Reproductive Medical Center, The Henan Province People's Hospital, Zhengzhou, China.
authors.forename: Duo
authors.initials: D
authors.lastname: Wei
authors.affiliation: Reproductive Medical Center, The Henan Province People's Hospital, Zhengzhou, China.
authors.forename: Lingling
authors.initials: L
authors.lastname: Liang
authors.affiliation: Reproductive Medical Center, The Henan Province People's Hospital, Zhengzhou, China.
authors.forename: Ke
authors.initials: K
authors.lastname: Feng
authors.affiliation: Reproductive Medical Center, The Henan Province People's Hospital, Zhengzhou, China.
authors.forename: Xiaobing
authors.initials: X
authors.lastname: Song
authors.affiliation: Reproductive Medical Center, The Henan Province People's Hospital, Zhengzhou, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Reproductive Medical Center, The Henan Province People's Hospital, Zhengzhou, China.
authors.forename: Bingbing
authors.initials: B
authors.lastname: Song
authors.affiliation: Reproductive Medical Center, The Henan Province People's Hospital, Zhengzhou, China.
authors.forename: Haoying
authors.initials: H
authors.lastname: Hao
authors.affiliation: Reproductive Medical Center, The Henan Province People's Hospital, Zhengzhou, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Reproductive Medical Center, The Henan Province People's Hospital, Zhengzhou, China.
authors.forename: Cuilian
authors.initials: C
authors.lastname: Zhang
mesh_terms: D000328:Adult; D019943:Amino Acid Substitution; D053713:Azoospermia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D024141:Collagen Type IV / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D008297:Male; D020125:Mutation, Missense; D014158:Transcription, Genetic / Q000235:genetics; D025721:WT1 Proteins / Q000235:genetics / Q000378:metabolism; D060528:Wnt4 Protein / Q000096:biosynthesis / Q000235:genetics
chemical_list: C547475:COL4A1 protein, human; D024141:Collagen Type IV; C555581:WNT4 protein, human; D025721:WT1 Proteins; C583751:WT1 protein, human; D060528:Wnt4 Protein