Fig. 6: Disruption of piRNA biogenesis causes spermatogenic failure in men.

a A schematic of piRNA biogenesis with the components affected among NOA cases in this study highlighted in red. piRNAs are produced by two biogenesis pathways. The primary pathway involves transcription of long precursor-transcripts from genomic clusters, which are then processed in the cytoplasm. b Cell scores for component 59, which encodes both piRNA processing genes and target pre-pre-piRNAs, indicate that it is expressed primarily in pre-leptotene spermatocytes. c Gene loadings for component 59. Note TDRD10 (black box), a protein-coding gene that has yet to be characterized for a role in mammalian piRNA processing. d H&E stain of TDRD9 patient biopsy showing spermatogenic arrest. The most mature germ cell observed were early round spermatids, which often appeared multinucleated (arrows). In addition, many pyknotic cells were observed (arrowheads). Scale bar = 50 µm. e Size distribution of piRNAs detected in the NOA case with a biallelic missense variant in TDRD12 and matching control, derived from small RNA-sequencing of testis tissue. f Significantly decreased fraction of mature (<32 bases) piRNAs was detected in testis of patients with piRNA pathway mutations, indicative of faulty processing of the immature piRNA transcripts.