Inherited defects of piRNA biogenesis cause transposon de-repression, impaired spermatogenesis, and human male infertility

Abstract Piwi-interacting RNAs (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 as novel disease genes. The testicular phenotypes repeatedly differ from those of the respective knockout mice and range from complete germ cell loss to the production of a few morphologically abnormal spermatozoa. LINE1 expression in spermatogonia links impaired piRNA biogenesis to transposon de-silencing and serves to classify variants as functionally relevant. Furthermore, an abolished expression of not only the encoded proteins but also of additional piRNA factors reveals co-dependencies within the human pathway. 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.