Variant <i>PNLDC1</i> , Defective piRNA Processing, and Azoospermia
Liina Nagirnaja, Nina Mørup, John Nielsen, Rytis Stakaitis, Ieva Golubickaitė, Manon S. Oud, Sofia Boeg Winge, Filipa Carvalho, Kenneth I. Aston, Francesca Khani, Godfried W. van der Heijden, C. Joana Marques, Niels E. Skakkebæk, Ewa Rajpert‐De Meyts, Peter N. Schlegel, Niklas Rye Jørgensen, Joris A. Veltman, Alexandra M. Lopes, Donald F. Conrad, Kristian Almstrup
Abstract
BACKGROUND: P-element-induced wimpy testis (PIWI)-interacting RNAs (piRNAs) are short (21 to 35 nucleotides in length) and noncoding and are found almost exclusively in germ cells, where they regulate aberrant expression of transposable elements and postmeiotic gene expression. Critical to the processing of piRNAs is the protein poly(A)-specific RNase-like domain containing 1 (PNLDC1), which trims their 3' ends and, when disrupted in mice, causes azoospermia and male infertility. METHODS: We performed exome sequencing on DNA samples from 924 men who had received a diagnosis of nonobstructive azoospermia. Testicular-biopsy samples were analyzed by means of histologic and immunohistochemical tests, in situ hybridization, reverse-transcriptase-quantitative-polymerase-chain-reaction assay, and small-RNA sequencing. RESULTS: mutations. CONCLUSIONS: Our results suggest a direct mechanistic effect of faulty piRNA processing on meiosis and spermatogenesis in men, ultimately leading to male infertility. (Funded by Innovation Fund Denmark and others.).