• PMID: 27990711
• Gene Name: WT1
• Condition: Idiopathic nonobstructive azoospermia (INOA), Male infertility
• Association: Associated
• Mutation: p.Phe435Leu (p.F435L)
• Population size: 400
• Population details: 400 (200 patients diagnosed with INOA, 200 proven-fertile men)
• Sex: Male
• Infertility type: Male infertility
• Other associated phenotypes: Idiopathic nonobstructive azoospermia (INOA), Male infertility

A novel functional variant in Wilms' Tumor 1 (WT1) is associated with idiopathic non-obstructive azoospermia

Xu J, Jiang L, Yu W, Guo H, Zhang H, Wei D, Liang L, Feng K, Song X, Liu Q, Song B, Hao H, Zhang Y, Zhang C.

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. CI - © 2017 Wiley Periodicals, Inc. FAU - Xu, Jin AU - Xu J AD - Reproductive Medical Center, The Henan Province People's Hospital, Zhengzhou, China. FAU - Jiang, Lile AU - Jiang L AD - Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, China. FAU - Yu, Wenzhu AU - Yu W AD - Reproductive Medical Center, The Henan Province People's Hospital, Zhengzhou, China. FAU - Guo, Haibin AU - Guo H AD - Reproductive Medical Center, The Henan Province People's Hospital, Zhengzhou, China. FAU - Zhang, Helong AU - Zhang H AD - Reproductive Medical Center, The Henan Province People's Hospital, Zhengzhou, China. FAU - Wei, Duo AU - Wei D AD - Reproductive Medical Center, The Henan Province People's Hospital, Zhengzhou, China. FAU - Liang, Lingling AU - Liang L AD - Reproductive Medical Center, The Henan Province People's Hospital, Zhengzhou, China. FAU - Feng, Ke AU - Feng K AD - Reproductive Medical Center, The Henan Province People's Hospital, Zhengzhou, China. FAU - Song, Xiaobing AU - Song X AD - Reproductive Medical Center, The Henan Province People's Hospital, Zhengzhou, China. FAU - Liu, Qi AU - Liu Q AD - Reproductive Medical Center, The Henan Province People's Hospital, Zhengzhou, China. FAU - Song, Bingbing AU - Song B AD - Reproductive Medical Center, The Henan Province People's Hospital, Zhengzhou, China. FAU - Hao, Haoying AU - Hao H AD - Reproductive Medical Center, The Henan Province People's Hospital, Zhengzhou, China. FAU - Zhang, Ying AU - Zhang Y AD - Reproductive Medical Center, The Henan Province People's Hospital, Zhengzhou, China.