Fiche publication
Date publication
août 2024
Journal
Nature communications
Auteurs
Membres identifiés du Cancéropôle Est :
Pr VIVILLE Stéphane
,
Dr LE MAY Nicolas
Tous les auteurs :
Stallmeyer B, Bühlmann C, Stakaitis R, Dicke AK, Ghieh F, Meier L, Zoch A, MacKenzie MacLeod D, Steingröver J, Okutman Ö, Fietz D, Pilatz A, Riera-Escamilla A, Xavier MJ, Ruckert C, Di Persio S, Neuhaus N, Gurbuz AS, Şalvarci A, Le May N, McEleny K, Friedrich C, van der Heijden G, Wyrwoll MJ, Kliesch S, Veltman JA, Krausz C, Viville S, Conrad DF, O'Carroll D, Tüttelmann F
Lien Pubmed
Résumé
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.
Mots clés
Male, Humans, Spermatogenesis, genetics, Infertility, Male, genetics, RNA, Small Interfering, metabolism, DNA Transposable Elements, genetics, Animals, Testis, metabolism, Mice, Adult, Gene Silencing, Mice, Knockout, Argonaute Proteins, metabolism, Long Interspersed Nucleotide Elements, genetics, Spermatogonia, metabolism, DEAD-box RNA Helicases, genetics, Piwi-Interacting RNA
Référence
Nat Commun. 2024 08 9;15(1):6637
