A homozygous PIWIL1 frameshift variant triggers azoospermia and reveals a strong selective constraint on germline...

PIWI proteins and their associated piRNAs constitute a highly conserved pathway that is essential for maintaining germline genome integrity through transposon silencing, viral defence, and RNA protection in germ cells. In mammals, defects in this pathway might lead to meiotic failure and infertility. However, the contributions of individual PIWI genes to human spermatogenesis remain poorly defined.

Here, we report on a 29-year-old man with non-obstructive azoospermia and found to carry a homozygous frameshift mutation in PIWIL1 (NM_004764.5:c.1176_1179delAACT). Histological examination of testicular tissue revealed spermatogenic arrest at the spermatocyte stage, and immunohistochemistry confirmed the absence of the full-length PIWIL1 protein and the absence of spermatids. Considering the low reported variant frequency for such a highly conserved mechanism, we evaluated the genetic constraints on PIWIL1.  A comparison of mRNA and amino acid sequences in the human vs. the great apes revealed the likely presence of purifying selective pressure.

Taken as a whole, these data reinforce the body of evidence showing that PIWIL1 is essential for human spermatogenesis and highlight the importance of the piRNA pathway in safeguarding the male germline. Defects in genome defence mechanisms might therefore constitute an underexplored cause of human male infertility.