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.