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Lookup NU author(s): Professor Joris VeltmanORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© The Author(s) 2024.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.
Author(s): Stallmeyer B, Buhlmann C, Stakaitis R, Dicke A-K, Ghieh F, Meier L, Zoch A, MacKenzie MacLeod D, Steingrover J, Okutman O, Fietz D, Pilatz A, Riera-Escamilla A, Xavier MJ, Ruckert C, Di Persio S, Neuhaus N, Gurbuz AS, Salvarci 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, Tuttelmann F
Publication type: Article
Publication status: Published
Journal: Nature Communications
Year: 2024
Volume: 15
Issue: 1
Online publication date: 09/08/2024
Acceptance date: 24/07/2024
Date deposited: 20/08/2024
ISSN (electronic): 2041-1723
Publisher: Nature Research
URL: https://doi.org/10.1038/s41467-024-50930-9
DOI: 10.1038/s41467-024-50930-9
Data Access Statement: Novel genetic variants described in this study have been deposited in ClinVar, the corresponding accession codes and permanent links are provided in Supplementary Data 4. Previously published variants in FKBP6 are available in ClinVar under accession numbers SCV002507290 [https://www.ncbi.nlm.nih.gov/clinvar/variation/1684032], SCV002507292 [https://www.ncbi.nlm.nih.gov/clinvar/variation/1684033], and SCV002507294 [https://www.ncbi.nlm.nih.gov/clinvar/variation/1684034]. [continues at https://www.nature.com/articles/s41467-024-50930-9#data-availability]
PubMed id: 39122675
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