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Research Paper|Volume 11, Issue 24|pp 12581—12599

FOXP3 pathogenic variants cause male infertility through affecting the proliferation and apoptosis of human spermatogonial stem cells

Qianqian Qiu1, Xing Yu2, Chencheng Yao3, Yujun Hao1, Liqing Fan4,5, Chunyi Li6, Peng Xu6, Geng An7, Zheng Li3, Zuping He2,8,9
  • 1State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
  • 2Hunan Normal University School of Medicine, Changsha, Hunan, China
  • 3Department of Andrology, The Center for Men's Health, Urologic Medical Center, Shanghai Key Laboratory of Reproductive Medicine, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai, China
  • 4Institute of Reproductive and Stem Cell Engineering, School of Basic Medical Science, Central South University, Changsha, China
  • 5Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha, China
  • 6Fertility Center, Shenyang Dongfang Jinghua Hospital, Shenyang, Liaoning, China
  • 7Department of Reproductive Medicine, Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
  • 8Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
  • 9Shanghai Key Laboratory of Reproductive Medicine, Shanghai, China
Received: September 17, 2019Accepted: November 26, 2019Published: December 19, 2019
https://doi.org/10.18632/aging.102589

Copyright © 2019 Qiu et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Genetic causes of male infertility that is associated with aging are largely unknown. This study was designed to identify novel pathogenic variants of FOXP3 gene causing azoospermia. One homozygous (c.155 G > T) pathogenic variant of FOXP3 was identified in nine non-obstructive azoospermia patients, and one heterozygous (c.691 C > A) of FOXP3 was found in one non-obstructive azoospermia patient. Pedigrees studies indicated that the homozygous (c.155 G > T) FOXP3 pathogenic variant was inherited, while heterozygous (c.691 C > A) FOXP3 pathogenic variant was acquired. Human testis carrying pathogenic variant exhibited abnormal spermatogenesis. FOXP3 protein was expressed at a lower level or undetected in spermatocytes of mutant testis of non-obstructive azoospermia patients compared to obstructive azoospermia patients. FOXP3 stimulated the proliferation and inhibited the apoptosis of human spermatogonial stem cells, and we further analyzed the targets of FOXP3. We have identified two new pathogenic variants of FOXP3 in non-obstructive azoospermia patients with high incidence, and FOXP3 silencing inhibits the proliferation and enhances the apoptosis of human spermatogonial stem cells. This study provides new insights into the etiology of azoospermia and offers novel pathogenic variants for gene targeting of male infertility.