Variant PNLDC1, Defective piRNA Processing, and Azoospermia

This study investigated the role of PNLDC1, a protein critical for piRNA processing, in male infertility. Exome sequencing was performed on DNA samples from 924 men diagnosed with nonobstructive azoospermia, identifying four unrelated men of Middle Eastern descent carrying mutations in PNLDC1. Testicular biopsies revealed defective meiosis and spermatogenic arrest, with round spermatids as the most advanced germ cell population. Expression of PNLDC1 and key piRNA-processing proteins (PIWIL1, PIWIL4, MYBL1, TDRKH) was significantly reduced in testicular cells. Small-RNA sequencing showed altered piRNA length distribution and reduced pachytene piRNAs in mutation carriers. The findings demonstrate that PNLDC1 mutations disrupt piRNA processing, leading to meiotic errors and spermatogenic arrest, ultimately causing nonobstructive azoospermia. This study highlights the mechanistic link between defective piRNA processing and male infertility, providing insights into genetic causes of azoospermia.

This study investigated the role of PNLDC1, a protein critical for piRNA processing, in male infertility. Exome sequencing was performed on DNA samples from 924 men diagnosed with nonobstructive azoospermia, identifying four unrelated men of Middle Eastern descent carrying mutations in PNLDC1. Testicular biopsies revealed defective meiosis and spermatogenic arrest, with round spermatids as the most advanced germ cell population. Expression of PNLDC1 and key piRNA-processing proteins (PIWIL1, PIWIL4, MYBL1, TDRKH) was significantly reduced in testicular cells. Small-RNA sequencing showed altered piRNA length distribution and reduced pachytene piRNAs in mutation carriers. The findings demonstrate that PNLDC1 mutations disrupt piRNA processing, leading to meiotic errors and spermatogenic arrest, ultimately causing nonobstructive azoospermia. This study highlights the mechanistic link between defective piRNA processing and male infertility, providing insights into genetic causes of azoospermia.