Variant PNLDC1, Defective piRNA Processing, and Azoospermia

• Type: Article in International Scientific Journal
• Date: 2021

Authors

Nagirnaja, L (Author) Other; Morup, N (Author) Other; Nielsen, JE (Author) Other; Stakaitis, R (Author) Other; Golubickaite, I (Author) Other; Oud, MS (Author) Other; Winge, SB (Author) Other; carvalho, f (Author) FMUP; Aston, KI (Author) Other; Khani, F (Author) Other; van der Heijden, GW (Author) Other; Marques, CJ (Author) FMUP; Skakkebaek, NE (Author) Other; Rajpert De Meyts, E (Author) Other; Schlegel, PN (Author) Other; Jorgensen, N (Author) Other; Veltman, JA (Author) Other; Alexandra M Lopes (Author) Other; Conrad, DF (Author) Other; Almstrup, K (Author) Other

Journal

Title: New England Journal of Medicine

Vol. 385

Pages: 707-719

ISSN: 0028-4793

Publisher: Massachusetts Medical Society

Indexing

ISI Web of Knowledge - 50 Citations

Scopus - 50 Citations

Other information

Authenticus ID: P-00V-907

DOI: 10.1056/nejmoa2028973

Abstract (EN): 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 Four unrelated men of Middle Eastern descent who had nonobstructive azoospermia were found to carry mutations in PNLDC1: the first patient had a biallelic stop-gain mutation, p.R452Ter (rs200629089; minor allele frequency, 0.00004); the second, a novel biallelic missense variant, p.P84S; the third, two compound heterozygous mutations consisting of p.M259T (rs141903829; minor allele frequency, 0.0007) and p.L35PfsTer3 (rs754159168; minor allele frequency, 0.00004); and the fourth, a novel biallelic canonical splice acceptor site variant, c.607-2A.T. Testicular histologic findings consistently showed error-prone meiosis and spermatogenic arrest with round spermatids of type Sa as the most advanced population of germ cells. Gene and protein expression of PNLDC1, as well as the piRNA-processing proteins PIWIL1, PIWIL4, MYBL1, and TDRKH, were greatly diminished in cells of the testes. Furthermore, the length distribution of piRNAs and the number of pachytene piRNAs was significantly altered in men carrying PNLDC1 mutations. CONCLUSIONS Our results suggest a direct mechanistic effect of faulty piRNA processing on meiosis and spermatogenesis in men, ultimately leading to male infertility.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 13