Nature Communications (Aug 2024)
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 Di Persio,
- Nina Neuhaus,
- Ali Sami Gurbuz,
- Ahmet Şalvarci,
- Nicolas Le May,
- Kevin McEleny,
- Corinna Friedrich,
- Godfried van der Heijden,
- Margot J. Wyrwoll,
- Sabine Kliesch,
- Joris A. Veltman,
- Csilla Krausz,
- Stéphane Viville,
- Donald F. Conrad,
- Dónal O’Carroll,
- Frank Tüttelmann
Affiliations
- Birgit Stallmeyer
- Centre of Medical Genetics, Institute of Reproductive Genetics, University of Münster
- Clara Bühlmann
- Centre of Medical Genetics, Institute of Reproductive Genetics, University of Münster
- Rytis Stakaitis
- Division of Genetics, Oregon National Primate Research Center, Oregon Health & Science University
- Ann-Kristin Dicke
- Centre of Medical Genetics, Institute of Reproductive Genetics, University of Münster
- Farah Ghieh
- Centre of Medical Genetics, Institute of Reproductive Genetics, University of Münster
- Luisa Meier
- Centre of Medical Genetics, Institute of Reproductive Genetics, University of Münster
- Ansgar Zoch
- Centre for Regenerative Medicine, Institute for Stem Cell Research, School of Biological Sciences, University of Edinburgh
- David MacKenzie MacLeod
- Centre for Regenerative Medicine, Institute for Stem Cell Research, School of Biological Sciences, University of Edinburgh
- Johanna Steingröver
- Centre of Medical Genetics, Institute of Reproductive Genetics, University of Münster
- Özlem Okutman
- Laboratoire de Génétique Médicale LGM, institut de génétique médicale d’Alsace IGMA, INSERM UMR 1112, Université de Strasbourg
- Daniela Fietz
- Institute of Veterinary Anatomy, Histology and Embryology, Justus-Liebig-Universität Gießen
- Adrian Pilatz
- Clinic for Urology, Paediatric Urology and Andrology, Justus Liebig University Gießen
- Antoni Riera-Escamilla
- Andrology Department, Fundació Puigvert, Universitat Autònoma de Barcelona, Instituto de Investigaciones Biomédicas Sant Pau
- Miguel J. Xavier
- Biosciences Institute, Faculty of Medical Sciences, Newcastle University
- Christian Ruckert
- Centre of Medical Genetics, Department of Medical Genetics, University of Münster
- Sara Di Persio
- Centre of Reproductive Medicine and Andrology, Department of Clinical and Surgical Andrology, University Hospital Münster
- Nina Neuhaus
- Centre of Reproductive Medicine and Andrology, Department of Clinical and Surgical Andrology, University Hospital Münster
- Ali Sami Gurbuz
- Department of Gynecology and Obstetrics Novafertil IVF Center
- Ahmet Şalvarci
- Department of Andrology Novafertil IVF Center
- Nicolas Le May
- Laboratoire de Génétique Médicale LGM, institut de génétique médicale d’Alsace IGMA, INSERM UMR 1112, Université de Strasbourg
- Kevin McEleny
- Newcastle Fertility Centre, The Newcastle upon Tyne Hospitals NHS Foundation Trust
- Corinna Friedrich
- Centre of Medical Genetics, Institute of Reproductive Genetics, University of Münster
- Godfried van der Heijden
- Department of Obstetrics and Gynecology, Radboud University Medical Center
- Margot J. Wyrwoll
- Centre of Medical Genetics, Institute of Reproductive Genetics, University of Münster
- Sabine Kliesch
- Centre of Reproductive Medicine and Andrology, Department of Clinical and Surgical Andrology, University Hospital Münster
- Joris A. Veltman
- Biosciences Institute, Faculty of Medical Sciences, Newcastle University
- Csilla Krausz
- Andrology Department, Fundació Puigvert, Universitat Autònoma de Barcelona, Instituto de Investigaciones Biomédicas Sant Pau
- Stéphane Viville
- Laboratoire de Génétique Médicale LGM, institut de génétique médicale d’Alsace IGMA, INSERM UMR 1112, Université de Strasbourg
- Donald F. Conrad
- Division of Genetics, Oregon National Primate Research Center, Oregon Health & Science University
- Dónal O’Carroll
- Centre for Regenerative Medicine, Institute for Stem Cell Research, School of Biological Sciences, University of Edinburgh
- Frank Tüttelmann
- Centre of Medical Genetics, Institute of Reproductive Genetics, University of Münster
- DOI
- https://doi.org/10.1038/s41467-024-50930-9
- Journal volume & issue
-
Vol. 15,
no. 1
pp. 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.
