Inherited defects of piRNA biogenesis cause transposon de-repression, impaired spermatogenesis, and human male infertility
Open accessPublished version of a preprint
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.
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Jumper, J., Evans, R., Pritzel, A., Green, T., Figurnov, M., Ronneberger, O., Tunyasuvunakool, K., Bates, R., Žídek, A., Potapenko, A., et al. (2021) · Nature · doi:10.1038/s41586-021-03819-2 · Cited by 43,764 · see citing works
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Mirdita, M., Schütze, K., Moriwaki, Y., Heo, L., Ovchinnikov, S., & Steinegger, M. (2021) · doi:10.1101/2021.08.15.456425 · Cited by 9,391 · see citing works
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- Authors
- Stallmeyer, B., Bühlmann, C., Stakaitis, R., Dicke, A.-K., Ghieh, F., Meier, L., Zoch, A., MacKenzie MacLeod, D., Steingröver, J., Okutman, Ö., Fietz, D., Pilatz, A., Riera-Escamilla, A., Xavier, M. J., Ruckert, C., Di Persio, S., Neuhaus, N., Gurbuz, A. S., Şalvarci, A., Le May, N., McEleny, K., Friedrich, C., van der Heijden, G., Wyrwoll, M. J., Kliesch, S., Veltman, J. A., Krausz, C., Viville, S., Conrad, D. F., O’Carroll, D., & Tüttelmann, F.
- Affiliations
- University of Münster (DE)
- Oregon National Primate Research Center (US)
- MRC Centre for Regenerative Medicine (GB)
- Université Libre de Bruxelles (BE)
- Justus-Liebig-Universität Gießen (DE)
- Newcastle University (GB)
- University Hospital Münster (DE)
- Newcastle upon Tyne Hospitals NHS Foundation Trust (GB)
- Universitat Autònoma de Barcelona (ES)
- Inserm (FR)
- Corresponding author
- Tüttelmann, Frank
- ORCID
- Stakaitis, Rytis
- Dicke, Ann-Kristin
- Ghieh, Farah
- Zoch, Ansgar
- Steingröver, Johanna
- Okutman, Özlem
- Fietz, Daniela
- Pilatz, Adrian
- Riera-Escamilla, Antoni
- Xavier, Miguel J.
- Neuhaus, Nina
- 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
- Venue
- Nature Communications
- Published
- 2024-08-09
- Volume
- 15
- Issue
- 1
- Pages
- 6637-6637
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC11316121
- OpenAlex
- W4401461449
- Cited by
- 71
- References
- 2
- Citations by year
- 2026: 29 · 2025: 36 · 2024: 6
- FWCI
- 27.83
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Nature Communications (publishedVersion, cc-by-nc-nd)
- Research Square (acceptedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Florence Research (University of Florence) (submittedVersion, cc-by-nc-nd)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, cc-by)
- Radboud Repository (Radboud University) (submittedVersion, cc-by-nc-nd)
- Lithuanian University of Health Sciences (submittedVersion, cc-by-nc-nd)
- RePEc: Research Papers in Economics (submittedVersion)
- Dipòsit Digital de Documents de la UAB (Universitat Autònoma de Barcelona) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- IRIS Research product catalog (Sapienza University of Rome) (submittedVersion, other-oa)
- Newcastle University ePrints (Newcastle Univesity) (cc-by)
- Funders
- Deutsche Forschungsgemeinschaft (CRU326, 329621271)
- Bundesministerium für Bildung und Forschung (01GR2303)
- Centre for Clinical Research Münster
- Topics
- Health Sciences › Medicine › Reproductive Medicine › Sperm and Testicular Function
- Life Sciences › Agricultural and Biological Sciences › Plant Science › Chromosomal and Genetic Variations
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Reproductive Biology and Fertility
- Keywords
- piRNA biogenesis, male infertility, transposon silencing, spermatogenesis, LINE-1, PIWIL1, MAEL, DDX4, germ cell maturation, spermatogonia, inherited genetic variants
- MeSH terms
- Piwi-Interacting RNA, Adult, Animals, DNA Transposable Elements, Humans, Infertility, Male, Male, Spermatogenesis, Spermatogonia, Testis, Mice, Knockout, Long Interspersed Nucleotide Elements, Gene Silencing, RNA, Small Interfering, Mice, DEAD-box RNA Helicases, Argonaute Proteins
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