Ann-Kristin Dicke

NXT2 is a key component of the RNA nuclear export factor complex in the human testis and essential for spermatogenesis | Nature Communications 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 i

NXT2, vital in RNA export in human testes, interacts with key nucleocytoplasmic components, including NXF1, NXF2, and NXF3, crucial for spermatogenesis. PMID:40624043, Nat Commun 2025, @NatureComms https://doi.org/10.1038/s41467-025-61463-0 #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

We conclude that the NXT-NXF pathway in the human testis is essential for male fertility and that NXT2 is an azoospermia candidate gene. More details in the paper! Thanks to all co-authors for their contributions and especially to @bstallmey.bsky.social and @ftuettelmann.bsky.social!

We next found an infertile man with a loss-of-function variant in NXF3. NXF3 is also X-chromosomal and a testis-expressed paralog of NXF1. The variant abolished the binding ability of NXF3 to NXT2. The affected man had few sperm with structural abnormalities.

Two men showed loss-of-function variants – RU00285 had a de novo deletion of entire NXT2 and M3065 shared a stop-gain variant with two (also infertile) brothers while the fertile brother and father did not show the variant which is thus segregating with the familial infertility.

But does disrupted NXT2 lead to male infertility? We queried our MERGE cohort and the #IMIGC cohorts to identify high impact variants in NXT2. Indeed, three men were showing hemizygous high impact variants, azoospermia and a concordant Sertoli cell-only phenotype.

Ubiquitous RNA export is mediated by the NXT1-NXF1 heterodimer. We pulled down the testis expressed paralog of NXT1, NXT2, from human testis tissue and show that not only NXF1, but testis paralogs NXF2 and NXF3 are interactors suggesting alternative export pathways in the testis.

NXT2 is a key component of the RNA nuclear export factor complex in the human testis and essential for spermatogenesis - Nature Communications The study introduces NXT2 as a candidate gene for male infertility and shows that the encoded protein is involved in RNA nucleocytoplasmic transport in human testis by interacting with the RNA export ...

You probably know that NXT1-NXF1 are important for RNA nuclear export, right? We show that NXT1s testis-specific paralog NXT2 is a key player for nuclear export in the human testis and link disruption of NXT2 to human male infertility. Out now in NatComm: rdcu.be/evh52 and more information below!⬇️

Great story by my friend @nadjarotte.bsky.social out in EMBO MolMed! Congratulations! Check it out here 👇🏽