Variant PNLDC1, Defective piRNA Processing, and Azoospermia

Data de publicação: Data Ahead of Print:

Autores da FMUP

  • Filipa Abreu Gomes De Carvalho

    Autor

  • Cristina Joana Moreira Marques

    Autor

Participantes de fora da FMUP

  • Nagirnaja, L
  • Morup, N
  • Nielsen, JE
  • Stakaitis, R
  • Golubickaite, I
  • Oud, MS
  • Winge, SB
  • Aston, KI
  • Khani, F
  • van der Heijden, GW
  • Skakkebaek, NE
  • Rajpert De Meyts, E
  • Schlegel, PN
  • Jorgensen, N
  • Veltman, JA
  • Lopes, A.
  • Conrad, DF
  • Almstrup, K

Unidades de investigação

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 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.

Dados da publicação

ISSN/ISSNe:
0028-4793, 1533-4406

New England Journal of Medicine  Massachussetts Medical Society

Tipo:
Article
Páginas:
707-719
Link para outro recurso:
www.scopus.com

Citações Recebidas na Web of Science: 49

Citações Recebidas na Scopus: 69

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Keywords

  • HOMOZYGOSITY; ASSOCIATION; INFERTILITY; GUIDELINES; DISORDERS; FERTILITY; DIAGNOSIS

Financiamento

Proyectos asociados

Epigenetic and transcriptional analysis ofTSC2 in leukocyte DNA from tuberous sclerosis patients.

Investigador Principal: Cristina Joana Moreira Marques

Estudo Observacional Académico (Epigenetic TSA) . Tuberous Sclerosis Association . 2019

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