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Lookup NU author(s): Oguzhan Kalyon, Professor Joris Veltman
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© The Author(s) 2025.In eukaryotes, the nucleocytoplasmic export of bulk poly(A)+-mRNAs through the nuclear pore complex is mediated by the ubiquitously expressed NXT1-NXF1 heterodimer. In humans, NXT1 has an X-chromosomal paralog, NXT2, which exhibits testis-enriched expression, suggesting a role in spermatogenesis. Here, we report the in vivo interaction of NXT2 with crucial components of the nuclear export machinery, including NXF1, the testis-specific NXF1 paralogs NXF2 and NXF3, and nuclear pore complex proteins. Binding to NXF2 and NXF3 is mediated by the NTF2-like domain of NXT2. By identifying infertile men with loss-of-function variants in NXT2 and NXF3, we link the impaired NXT2-NXF activity to disturbed germ cell development. The predominant absence of germ cells in men with NXT2 deficiency indicates its critical function already during fetal or first steps of germ cell development. In contrast, loss of NXF3 affects later stages of spermatogenesis, resulting in quantitatively and qualitatively impaired sperm production.
Author(s): Dicke A-K, Ahmedani A, Ma L, Herrmann L, van der Heijden GW, Koser SA, Krallmann C, Kalyon O, Xavier MJ, Veltman JA, Kliesch S, Neuhaus N, Kotaja N, Tuttelmann F, Stallmeyer B
Publication type: Article
Publication status: Published
Journal: Nature Communications
Year: 2025
Volume: 16
Issue: 1
Online publication date: 07/07/2025
Acceptance date: 24/06/2025
Date deposited: 22/07/2025
ISSN (electronic): 2041-1723
Publisher: Nature Research
URL: https://doi.org/10.1038/s41467-025-61463-0
DOI: 10.1038/s41467-025-61463-0
Data Access Statement: Submission of human exome/genome sequencing data from the MERGE cohort to public databases is not covered by the probands informed consent. These data will be available upon request for academic use and within the limitations of the proband’s informed consent from the Frank Tüttelmnn, Director of the Institute of Reproductive Genetics, Münster, Germany, by contacting frank.tuettelmann@ukmuenster.de. Each request will be reviewed within 1 month and the researcher will need to sign a data access agreement. [further details at https://www.nature.com/articles/s41467-025-61463-0#data-availability ]
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