Variant PNLDC1, Defective piRNA Processing, and Azoospermia

• Tipo: Artigo em Revista Científica Internacional
• Data: 2021

Autores

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

Revista

Título: New England Journal of Medicine

Vol. 385

Páginas: 707-719

ISSN: 0028-4793

Editora: Massachusetts Medical Society

Indexação

ISI Web of Knowledge - 59 Citações

Scopus - 61 Citações

Outras Informações

ID Authenticus: 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.

Idioma: Inglês

Tipo (Avaliação Docente): Científica

Nº de páginas: 13