PDF(Pubmed)
Abstract：
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. In some affected men, the testicular phenotypes differ from those of the respective knockout mice and range from complete germ cell loss to the production of a few morphologically abnormal sperm. A reduced number of pachytene piRNAs was detected in the testicular tissue of variant carriers, demonstrating impaired piRNA biogenesis. Furthermore, LINE1 expression in spermatogonia links impaired piRNA biogenesis to transposon de-silencing and serves to classify variants as functionally relevant. 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.
摘要：
piRNAs对于转座子沉默至关重要，生殖细胞成熟,和雄性小鼠的生育能力。这里,我们报告了人类piRNA功能障碍的遗传景观，并介绍了39名不育男性携带14种不同piRNA通路基因的双等位基因变异，包括PIWIL1、GTSF1、GPAT2、MAEL、TDRD1和DDX4。在一些受影响的男人中，睾丸表型与相应基因敲除小鼠的表型不同，范围从生殖细胞完全丧失到产生一些形态异常的精子。在变异携带者的睾丸组织中检测到数量减少的粗线质piRNAs，显示piRNA生物发生受损。此外，精原细胞中的LINE1表达将受损的piRNA生物发生与转座子去沉默联系起来，并用于将变体分类为功能相关。这些结果确立了被破坏的piRNA途径是人类生精失败的主要原因，并提供了对人类男性生殖细胞中转座子沉默的见解。
