Functional Investigation of a Novel PIWIL4 Mutation in Nonobstructive Azoospermia During the First Wave of Spermatogenesis
PIWI-interacting RNAs (piRNAs) are small noncoding RNAs that are almost exclusively expressed in germ cells to silence harmful transposons to maintain genome stability. PIWIL4 is guided by its associated piRNAs to transposable elements, where it recruits the DNA methylation apparatus and instructs d...
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MDPI AG
2025-02-01
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| Series: | Biomolecules |
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| Online Access: | https://www.mdpi.com/2218-273X/15/2/297 |
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| author | Xiayu Wang Qian Du Wanqian Li Zhongyu Zou Chikun Wang Yan Zhou Zhibin Hu Yayun Gu Feng Li |
| author_facet | Xiayu Wang Qian Du Wanqian Li Zhongyu Zou Chikun Wang Yan Zhou Zhibin Hu Yayun Gu Feng Li |
| author_sort | Xiayu Wang |
| collection | DOAJ |
| description | PIWI-interacting RNAs (piRNAs) are small noncoding RNAs that are almost exclusively expressed in germ cells to silence harmful transposons to maintain genome stability. PIWIL4 is guided by its associated piRNAs to transposable elements, where it recruits the DNA methylation apparatus and instructs de novo DNA methylation. Herein, we identified a missense variant of <i>PIWIL4</i> (c.805 C>T p.R269W) in two infertile males. Homozygous male mice carrying the orthologous knock-in variant displayed elevated transposable element expression and aberrant gene expression during the first wave of spermatogenesis, despite exhibiting normal sperm counts and morphology. Mechanistically, the mutated site altered the piRNA-binding ability of PIWIL4 and led to the derepression of endogenous LINE-1 elements. In summary, we identified a piRNA binding mutation in PIWIL4 that may be involved in human nonobstructive azoospermia. |
| format | Article |
| id | doaj-art-560394e6a18841e59db2d6dcccd65de5 |
| institution | DOAJ |
| issn | 2218-273X |
| language | English |
| publishDate | 2025-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomolecules |
| spelling | doaj-art-560394e6a18841e59db2d6dcccd65de52025-08-20T02:44:31ZengMDPI AGBiomolecules2218-273X2025-02-0115229710.3390/biom15020297Functional Investigation of a Novel PIWIL4 Mutation in Nonobstructive Azoospermia During the First Wave of SpermatogenesisXiayu Wang0Qian Du1Wanqian Li2Zhongyu Zou3Chikun Wang4Yan Zhou5Zhibin Hu6Yayun Gu7Feng Li8State Key Laboratory of Reproductive Medicine and Offspring Health, Nanjing Medical University, Nanjing 211166, ChinaState Key Laboratory of Reproductive Medicine and Offspring Health, Nanjing Medical University, Nanjing 211166, ChinaState Key Laboratory of Reproductive Medicine and Offspring Health, Nanjing Medical University, Nanjing 211166, ChinaState Key Laboratory of Reproductive Medicine and Offspring Health, Nanjing Medical University, Nanjing 211166, ChinaState Key Laboratory of Reproductive Medicine and Offspring Health, Nanjing Medical University, Nanjing 211166, ChinaState Key Laboratory of Reproductive Medicine and Offspring Health, Nanjing Medical University, Nanjing 211166, ChinaState Key Laboratory of Reproductive Medicine and Offspring Health, Nanjing Medical University, Nanjing 211166, ChinaState Key Laboratory of Reproductive Medicine and Offspring Health, Nanjing Medical University, Nanjing 211166, ChinaState Key Laboratory of Reproductive Medicine and Offspring Health, Nanjing Medical University, Nanjing 211166, ChinaPIWI-interacting RNAs (piRNAs) are small noncoding RNAs that are almost exclusively expressed in germ cells to silence harmful transposons to maintain genome stability. PIWIL4 is guided by its associated piRNAs to transposable elements, where it recruits the DNA methylation apparatus and instructs de novo DNA methylation. Herein, we identified a missense variant of <i>PIWIL4</i> (c.805 C>T p.R269W) in two infertile males. Homozygous male mice carrying the orthologous knock-in variant displayed elevated transposable element expression and aberrant gene expression during the first wave of spermatogenesis, despite exhibiting normal sperm counts and morphology. Mechanistically, the mutated site altered the piRNA-binding ability of PIWIL4 and led to the derepression of endogenous LINE-1 elements. In summary, we identified a piRNA binding mutation in PIWIL4 that may be involved in human nonobstructive azoospermia.https://www.mdpi.com/2218-273X/15/2/297PIWIL4LINE-1infertilitymissense mutationspermatogenesisretrotransposon |
| spellingShingle | Xiayu Wang Qian Du Wanqian Li Zhongyu Zou Chikun Wang Yan Zhou Zhibin Hu Yayun Gu Feng Li Functional Investigation of a Novel PIWIL4 Mutation in Nonobstructive Azoospermia During the First Wave of Spermatogenesis Biomolecules PIWIL4 LINE-1 infertility missense mutation spermatogenesis retrotransposon |
| title | Functional Investigation of a Novel PIWIL4 Mutation in Nonobstructive Azoospermia During the First Wave of Spermatogenesis |
| title_full | Functional Investigation of a Novel PIWIL4 Mutation in Nonobstructive Azoospermia During the First Wave of Spermatogenesis |
| title_fullStr | Functional Investigation of a Novel PIWIL4 Mutation in Nonobstructive Azoospermia During the First Wave of Spermatogenesis |
| title_full_unstemmed | Functional Investigation of a Novel PIWIL4 Mutation in Nonobstructive Azoospermia During the First Wave of Spermatogenesis |
| title_short | Functional Investigation of a Novel PIWIL4 Mutation in Nonobstructive Azoospermia During the First Wave of Spermatogenesis |
| title_sort | functional investigation of a novel piwil4 mutation in nonobstructive azoospermia during the first wave of spermatogenesis |
| topic | PIWIL4 LINE-1 infertility missense mutation spermatogenesis retrotransposon |
| url | https://www.mdpi.com/2218-273X/15/2/297 |
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