piRNAs are crucial for transposon silencing, germ cell maturation, and fertility in male mice. Here, we report on the genetic landscape of piRNA dysfunction in humans and present 39 infertile men carrying biallelic variants in 14 different piRNA pathway genes, including PIWIL1, GTSF1, GPAT2, MAEL, TDRD1, and DDX4. In some affected men, the testicular phenotypes differ from those of the respective knockout mice and range from complete germ cell loss to the production of a few morphologically abnormal sperm. A reduced number of pachytene piRNAs was detected in the testicular tissue of variant carriers, demonstrating impaired piRNA biogenesis. Furthermore, LINE1 expression in spermatogonia links impaired piRNA biogenesis to transposon de-silencing and serves to classify variants as functionally relevant. These results establish the disrupted piRNA pathway as a major cause of human spermatogenic failure and provide insights into transposon silencing in human male germ cells.piRNAs are small RNA molecules found primarily in the testes of mice and men. Stallmeyer et al. demonstrate that variants in specific genes can disrupt the formation of piRNAs, impairing spermatogenesis and causing human male infertility.

Inherited defects of piRNA biogenesis cause transposon de-repression, impaired spermatogenesis, and human male infertility / Stallmeyer, Birgit; Bühlmann, Clara; Stakaitis, Rytis; Dicke, Ann-Kristin; Ghieh, Farah; Meier, Luisa; Zoch, Ansgar; MacKenzie MacLeod, David; Steingröver, Johanna; Okutman, Özlem; Fietz, Daniela; Pilatz, Adrian; Riera-Escamilla, Antoni; Xavier, Miguel J; Ruckert, Christian; Di Persio, Sara; Neuhaus, Nina; Gurbuz, Ali Sami; Şalvarci, Ahmet; Le May, Nicolas; McEleny, Kevin; Friedrich, Corinna; van der Heijden, Godfried; Wyrwoll, Margot J; Kliesch, Sabine; Veltman, Joris A; Krausz, Csilla; Viville, Stéphane; Conrad, Donald F; O'Carroll, Dónal; Tüttelmann, Frank. - In: NATURE COMMUNICATIONS. - ISSN 2041-1723. - ELETTRONICO. - 15:(2024), pp. 6637.0-6637.0. [10.1038/s41467-024-50930-9]

Inherited defects of piRNA biogenesis cause transposon de-repression, impaired spermatogenesis, and human male infertility

Krausz, Csilla;
2024

Abstract

piRNAs are crucial for transposon silencing, germ cell maturation, and fertility in male mice. Here, we report on the genetic landscape of piRNA dysfunction in humans and present 39 infertile men carrying biallelic variants in 14 different piRNA pathway genes, including PIWIL1, GTSF1, GPAT2, MAEL, TDRD1, and DDX4. In some affected men, the testicular phenotypes differ from those of the respective knockout mice and range from complete germ cell loss to the production of a few morphologically abnormal sperm. A reduced number of pachytene piRNAs was detected in the testicular tissue of variant carriers, demonstrating impaired piRNA biogenesis. Furthermore, LINE1 expression in spermatogonia links impaired piRNA biogenesis to transposon de-silencing and serves to classify variants as functionally relevant. These results establish the disrupted piRNA pathway as a major cause of human spermatogenic failure and provide insights into transposon silencing in human male germ cells.piRNAs are small RNA molecules found primarily in the testes of mice and men. Stallmeyer et al. demonstrate that variants in specific genes can disrupt the formation of piRNAs, impairing spermatogenesis and causing human male infertility.
2024
15
0
0
Goal 3: Good health and well-being
Stallmeyer, Birgit; Bühlmann, Clara; Stakaitis, Rytis; Dicke, Ann-Kristin; Ghieh, Farah; Meier, Luisa; Zoch, Ansgar; MacKenzie MacLeod, David; Steingr...espandi
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Utilizza questo identificatore per citare o creare un link a questa risorsa: https://hdl.handle.net/2158/1399669
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