Inherited defects of piRNA biogenesis cause transposon de-repression, impaired spermatogenesis, and human male infertility-Reference-Cited by-同舟云学术

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

Published:2024-01-09 Issue: Volume: Page:
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Author:

Stallmeyer Birgit¹,Bühlmann Clara¹,Stakaitis Rytis²,Dicke Ann-Kristin¹^ORCID,Ghieh Farah¹,Meier Luisa¹,Zoch Ansgar³,MacLeod David MacKenzie³,Steingröver Johanna¹,Okutman Özlem⁴,Fietz Daniela⁵,Pilatz Adrian⁶^ORCID,Escamilla Antoni Riera⁷^ORCID,Xavier Miguel⁸^ORCID,Ruckert Christian⁹,Persio Sara Di¹⁰,Neuhaus Nina¹⁰^ORCID,Gurbuz Ali Sami¹¹,Şalvarci Ahmend¹²,May Nicolas Le¹³,McEleny Kevin¹⁴,Friedrich Corinna¹,Heijden Godfried van der¹⁵^ORCID,Wyrwoll Margot J.¹⁶,Kliesch Sabine¹⁰^ORCID,Veltman Joris A.⁸^ORCID,Krausz Csilla¹⁷,Viville Stéphane¹⁸,Conrad Donald¹⁹^ORCID,O'Carroll Donal³^ORCID,Tüttelmann Frank¹^ORCID

Affiliation:

1. Institute of Reproductive Genetics, University of Münster, 48149 Münster, Germany.

2. Division of Genetics, Oregon National Primate Research Center, Oregon Health & Science University, Portland, OR 97006, USA.; Laboratory of Molecular Neurooncology, Neuroscience Institute, Lithuanian University of Health Sciences, Kaunas 50161, Lithuania.

3. Centre for Regenerative Medicine, Institute for Stem Cell Research, School of Biological Sciences, University of Edinburgh, Edinburgh, UK.; Wellcome Centre for Cell Biology, School of Biological Sciences, The University of Edinburgh, UK.

4. Laboratoire de Génétique Médicale LGM, Institut de génétique médicale d’Alsace IGMA, INSERM UMR 1112; Université de Strasbourg, France. Université libre de Bruxelles (ULB), Hôpital Universitaire de Bruxelles, Hôpital Erasme, Service de Gynécologie-Obstetrique, Clinique de Fertilité, Bruxelles, Belgium.

5. Institute of Veterinary Anatomy, Histology and Embryology, Justus-Liebig-Universität Gießen

6. Clinic for Urology, Paediatric Urology and Andrology, Justus Liebig University Gießen, 35390 Gießen, Germany.

7. Andrology Department, Fundació Puigvert, Universitat Autònoma de Barcelona, Instituto de Investigaciones Biomédicas Sant Pau, Barcelona, 08025 Catalonia, Spain.

8. Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.

9. Institute of Human Genetics, University of Münster, 48149 Münster, Germany.

10. Centre of Reproductive Medicine and Andrology, University Hospital Münster, Münster 48149, Germany.

11. Department of Gynecology and Obstetrics Novafertil IVF Center, Konya, Turkey.

12. Department of Andrology Novafertil IVF Center, Konya, Turkey.

13. Laboratoire de Génétique Médicale LGM, Institut de génétique médicale d’Alsace IGMA, INSERM UMR 1112, Université de Strasbourg, France.

14. Newcastle Fertility Centre, The Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.

15. Department of Obstetrics and Gynecology, Radboud University Medical Center, Nijmegen, the Netherlands.

16. Institute of Reproductive Genetics, University of Münster, 48149 Münster, Germany.; Centre for Regenerative Medicine, Institute for Stem Cell Research, School of Biological Sciences, University of Edinburgh, Edinburgh, UK.

17. Andrology Department, Fundació Puigvert, Universitat Autònoma de Barcelona, Instituto de Investigaciones Biomédicas Sant Pau, Barcelona, 08025 Catalonia, Spain.; Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, University Hospital Careggi, Viale Pieraccini 6, Florence 50139, Italy.

18. Laboratoire de Génétique Médicale LGM, Institut de génétique médicale d’Alsace IGMA, INSERM UMR 1112, Université de Strasbourg, France.; Laboratoire de Diagnostic Génétique, UF3472-génétique de l'infertilité, Hôpitaux Universitaires de Strasbourg, 67000 Strasbourg, France.

19. Division of Genetics, Oregon National Primate Research Center, Oregon Health & Science University, Portland, OR 97006, USA.

Abstract

Abstract Piwi-interacting RNAs (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 as novel disease genes. The testicular phenotypes repeatedly differ from those of the respective knockout mice and range from complete germ cell loss to the production of a few morphologically abnormal spermatozoa. LINE1 expression in spermatogonia links impaired piRNA biogenesis to transposon de-silencing and serves to classify variants as functionally relevant. Furthermore, an abolished expression of not only the encoded proteins but also of additional piRNA factors reveals co-dependencies within the human pathway. 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.

Publisher

Research Square Platform LLC

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