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Variant PNLDC1, Defective piRNA Processing, and Azoospermia.

Liina Nagirnaja1, Nina Mørup1, John E Nielsen1

  • 1From the Division of Genetics, Oregon National Primate Research Center, Oregon Health and Science University, Beaverton (L.N., D.F.C.); the Center for Embryonic Cell and Gene Therapy, Oregon Health and Science University, Portland (D.F.C.); the Department of Growth and Reproduction (N.M., J.E.N., R.S., I.G., S.B.W., N.E.S., E.R.-D.M., N.J., K.A.) and the International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (N.M., J.E.N., R.S., I.G., S.B.W., N.E.S., E.R.-D.M., N.J., K.A.), Rigshospitalet, and the Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences (K.A.), University of Copenhagen, Copenhagen; the Laboratory of Molecular Neurooncology, Neuroscience Institute (R.S.), and the Institute of Biology Systems and Genetic Research (I.G.), Lithuanian University of Health Sciences, Kaunas, Lithuania; the Department of Human Genetics, Donders Institute for Brain, Cognition, and Behavior (M.S.O., G.W.H.), and the Department of Obstetrics and Gynecology (G.W.H.), Radboud University Medical Center, Nijmegen, the Netherlands; Serviço de Genética, Departamento de Patologia, Faculdade de Medicina da Universidade do Porto (F.C., C.J.M.), Instituto de Investigação e Inovação em Saúde, Universidade do Porto (F.C., C.J.M., A.M.L.), and the Institute of Molecular Pathology and Immunology of the University of Porto (A.M.L.) - all in Porto, Portugal; the Andrology and In Vitro Fertilization Laboratory, Department of Surgery (Urology), University of Utah School of Medicine, Salt Lake City (K.I.A.); the Departments of Pathology and Laboratory Medicine (F.K.) and Urology (P.N.S.), Weill Cornell Medicine, New York; and the Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom (J.A.V.).

The New England Journal of Medicine
|August 4, 2021
PubMed
Summary

Mutations in PNLDC1 cause male infertility by disrupting piRNA processing, leading to errors in meiosis and spermatogenesis. This study identifies PNLDC1 as a key gene in male fertility.

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Area of Science:

  • Genetics
  • Reproductive Biology
  • Molecular Biology

Background:

  • P-element-induced wimpy testis (PIWI)-interacting RNAs (piRNAs) are crucial for regulating gene expression in germ cells.
  • Poly(A)-specific RNase-like domain containing 1 (PNLDC1) is essential for piRNA processing, specifically trimming their 3' ends.
  • Disruption of PNLDC1 in mice leads to azoospermia and male infertility.

Purpose of the Study:

  • To investigate the role of PNLDC1 mutations in nonobstructive azoospermia in men.
  • To elucidate the mechanistic link between PNLDC1 dysfunction, piRNA processing, and male infertility.

Main Methods:

  • Exome sequencing of 924 men diagnosed with nonobstructive azoospermia.
  • Histologic, immunohistochemical, in situ hybridization, RT-qPCR, and small-RNA sequencing of testicular biopsy samples.
  • Genetic analysis of identified PNLDC1 variants.

Main Results:

  • Four unrelated men with nonobstructive azoospermia were found to have mutations in PNLDC1.
  • These mutations included stop-gain, missense, frameshift, and splice acceptor site variants.
  • PNLDC1 mutation carriers exhibited impaired meiosis, spermatogenic arrest, diminished PNLDC1 and piRNA pathway protein expression, and altered piRNA profiles.

Conclusions:

  • Faulty piRNA processing due to PNLDC1 mutations directly impacts meiosis and spermatogenesis.
  • PNLDC1 is a critical gene for male fertility, and its mutations are a cause of nonobstructive azoospermia.
  • These findings establish a mechanistic link between piRNA pathway dysfunction and male infertility.