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

Birgit Stallmeyer, Clara Bühlmann, Rytis Stakaitis, Ann-Kristin Dicke, Farah Ghieh, Luisa Meier, Ansgar Zoch, David MacKenzie MacLeod, Johanna Steingröver, Özlem Okutman, Daniela Fietz, Adrian Pilatz, Antoni Riera-Escamilla, Miguel J. Xavier, Christian Ruckert, Sara Persio, Nina Neuhaus, Ali Sami Gurbuz, Ahmet Şalvarci, Nicolas May, Kevin McEleny, Corinna Friedrich, Godfried Heijden, Margot J. Wyrwoll, Sabine Kliesch, Joris A. Veltman, Csilla Krausz, Stéphane Viville, Donald F. Conrad, Dónal O’Carroll and Frank Tüttelmann ()
Additional contact information
Birgit Stallmeyer: University of Münster
Clara Bühlmann: University of Münster
Rytis Stakaitis: Oregon Health & Science University
Ann-Kristin Dicke: University of Münster
Farah Ghieh: University of Münster
Luisa Meier: University of Münster
Ansgar Zoch: University of Edinburgh
David MacKenzie MacLeod: University of Edinburgh
Johanna Steingröver: University of Münster
Özlem Okutman: Université de Strasbourg
Daniela Fietz: Justus-Liebig-Universität Gießen
Adrian Pilatz: Justus Liebig University Gießen
Antoni Riera-Escamilla: Instituto de Investigaciones Biomédicas Sant Pau
Miguel J. Xavier: Newcastle University
Christian Ruckert: University of Münster
Sara Persio: University Hospital Münster
Nina Neuhaus: University Hospital Münster
Ali Sami Gurbuz: Department of Gynecology and Obstetrics Novafertil IVF Center
Ahmet Şalvarci: Department of Andrology Novafertil IVF Center
Nicolas May: Université de Strasbourg
Kevin McEleny: The Newcastle upon Tyne Hospitals NHS Foundation Trust
Corinna Friedrich: University of Münster
Godfried Heijden: Radboud University Medical Center
Margot J. Wyrwoll: University of Münster
Sabine Kliesch: University Hospital Münster
Joris A. Veltman: Newcastle University
Csilla Krausz: Instituto de Investigaciones Biomédicas Sant Pau
Stéphane Viville: Université de Strasbourg
Donald F. Conrad: Oregon Health & Science University
Dónal O’Carroll: University of Edinburgh
Frank Tüttelmann: University of Münster

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-50930-9

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