Inherited defects of piRNA biogenesis cause transposon de-repression, impaired spermatogenesis, and human male infertility
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.
Authors
- Nicolas Le May (ORCID: https://orcid.org/0000-0002-0172-8752)
- Adrian Pilatz (ORCID: https://orcid.org/0000-0001-8072-1841)
- Godfried W. van der Heijden (ORCID: https://orcid.org/0000-0001-5894-7027)
- Rytis Stakaitis (ORCID: https://orcid.org/0000-0001-5946-1731)
- Frank Tüttelmann (ORCID: https://orcid.org/0000-0003-2745-9965)
- Joris A. Veltman (ORCID: https://orcid.org/0000-0002-3218-8250)
- Daniela Fietz (ORCID: https://orcid.org/0000-0002-7945-1810)
- Johanna Steingröver (ORCID: https://orcid.org/0009-0007-2272-026X)
- Corinna Friedrich (ORCID: https://orcid.org/0000-0001-8848-3366)
- Antoni Riera‐Escamilla (ORCID: https://orcid.org/0000-0002-4485-3094)
- Sara Di Persio (ORCID: https://orcid.org/0000-0002-9279-7373)
- Ann‐Kristin Dicke (ORCID: https://orcid.org/0000-0002-2171-0525)
- Stéphane Viville (ORCID: https://orcid.org/0000-0002-5088-3003)
- Ansgar Zoch (ORCID: https://orcid.org/0000-0003-2071-1590)
- Donald F. Conrad (ORCID: https://orcid.org/0000-0003-3828-8970)
- Ahmet Şalvarcı (ORCID: https://orcid.org/0000-0002-5231-2415)
- Csilla Krausz (ORCID: https://orcid.org/0000-0001-6748-8918)
- Sabine Kliesch (ORCID: https://orcid.org/0000-0002-7561-4870)
- Christian Rückert (ORCID: https://orcid.org/0000-0002-9722-4435)
- Özlem Okutman (ORCID: https://orcid.org/0000-0002-3796-2479)
- Ali Sami Gürbüz (ORCID: https://orcid.org/0000-0001-7747-3074)
- Margot J. Wyrwoll (ORCID: https://orcid.org/0000-0002-7651-2403)
- Dónal O’Carroll (ORCID: https://orcid.org/0000-0002-8626-2217)
- Nina Neuhaus (ORCID: https://orcid.org/0000-0003-0181-6194)
- Miguel J. Xavier (ORCID: https://orcid.org/0000-0003-0709-7223)
- Kevin McEleny (ORCID: https://orcid.org/0000-0001-9827-8139)
- Birgit Stallmeyer
- Luisa Meier
- Clara Bühlmann
- Farah Ghieh
- David MacKenzie MacLeod
Institutions
- Oregon National Primate Research Center (US)
- Universitat Autònoma de Barcelona (ES)
- Lithuanian University of Health Sciences (LT)
- Université Libre de Bruxelles (BE)
- Radboud University Nijmegen (NL)
- Inserm (FR)
- Oregon Health & Science University (US)
- Justus-Liebig-Universität Gießen (DE)
- University of Münster (DE)
- Newcastle upon Tyne Hospitals NHS Foundation Trust (GB)
- Radboud University Medical Center (NL)
- University Hospital Münster (DE)
- MRC Centre for Regenerative Medicine (GB)
- Wellcome Centre for Cell Biology (GB)
- Puigvert Foundation (ES)
- Hôpitaux Universitaires de Strasbourg (FR)
- University of Florence (IT)
- Université de Strasbourg (FR)
- Newcastle University (GB)
- University of Edinburgh (GB)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-08-09
- DOI
- https://doi.org/10.1038/s41467-024-50930-9
- Citations
- 50
- Primary Topic
- Chromosomal and Genetic Variations
- Type
- article
- Field-Weighted Citation Impact
- 29.98
Funders
- Wellcome Trust
- Deutsche Forschungsgemeinschaft
- Bundesministerium für Bildung und Forschung
- Medizinische Fakultät, Westfälische Wilhelms-Universität Münster