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.
Nature communications. 2024 Aug 09*** epublish ***
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
Centre of Medical Genetics, Institute of Reproductive Genetics, University of Münster, Münster, Germany., Division of Genetics, Oregon National Primate Research Center, Oregon Health & Science University, Portland, OR, USA., Centre for Regenerative Medicine, Institute for Stem Cell Research, School of Biological Sciences, University of Edinburgh, Edinburgh, UK., Laboratoire de Génétique Médicale LGM, institut de génétique médicale d'Alsace IGMA, INSERM UMR 1112, Université de Strasbourg, Strasbourg, France., Institute of Veterinary Anatomy, Histology and Embryology, Justus-Liebig-Universität Gießen, Gießen, Germany., Clinic for Urology, Paediatric Urology and Andrology, Justus Liebig University Gießen, Gießen, Germany., Andrology Department, Fundació Puigvert, Universitat Autònoma de Barcelona, Instituto de Investigaciones Biomédicas Sant Pau, Barcelona, Catalonia, Spain., Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK., Centre of Medical Genetics, Department of Medical Genetics, University of Münster, Münster, Germany., Centre of Reproductive Medicine and Andrology, Department of Clinical and Surgical Andrology, University Hospital Münster, Münster, Germany., Department of Gynecology and Obstetrics Novafertil IVF Center, Konya, Turkey., Department of Andrology Novafertil IVF Center, Konya, Turkey., Newcastle Fertility Centre, The Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK., Department of Obstetrics and Gynecology, Radboud University Medical Center, Nijmegen, The Netherlands., Centre of Medical Genetics, Institute of Reproductive Genetics, University of Münster, Münster, Germany. .
PubMed http://www.ncbi.nlm.nih.gov/pubmed/39122675