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J Med Genet 50:187-193 doi:10.1136/jmedgenet-2012-101230
  • Developmental defects
  • Original article

Mutations of NANOS1, a human homologue of the Drosophila morphogen, are associated with a lack of germ cells in testes or severe oligo-astheno-teratozoospermia

  1. Jadwiga Jaruzelska1
  1. 1Polish Academy of Sciences, Institute of Human Genetics, Poznań, Poland
  2. 2Department and Chair of Medical Genetics, University of Medical Sciences, Poznań, Poland
  3. 3Division of Infertility and Reproductive Endocrinology, University of Medical Sciences, Poznań, Poland
  1. Correspondence to Professor Jadwiga Jaruzelska, Polish Academy of Sciences, Institute of Human Genetics, Strzeszyńska 32, Poznań 60-479, Poland; jaruzjad{at}man.poznan.pl
  • Received 10 August 2012
  • Revised 14 November 2012
  • Accepted 9 December 2012
  • Published Online First 12 January 2013

Abstract

Background The Nanos gene is a key translational regulator of specific mRNAs involved in Drosophila germ cell development. Disruption of mammalian homologues, Nanos2 or Nanos3, causes male infertility in mice. In humans, however, no evidence of NANOS2 or NANOS3 mutations causing male infertility has been reported. Although Nanos1 seems dispensable for mouse reproduction, we sought to analyse for the first time its homologue in infertile men.

Methods A group of 195 patients manifesting non-obstructive azoospermia or oligozoospermia were tested for mutations of the NANOS1 gene, using single-strand conformation polymorphism and DNA sequencing.

Results Three types of NANOS1 gene mutations were identified in five patients and were absent in 800 chromosomes of fertile men. Pedigree analysis indicated a dominant inheritance pattern with penetration limited to males. Two mutations caused deletions of single amino acids, p.Pro77_Ser78delinsPro and p.Ala173del, each of them identified in two unrelated patients. Both types of deletions were located in the NANOS1 N-terminus (responsible for protein interactions) and were associated with a lack of germ cells in testes. Interestingly, the Pro77_Ser78delinsPro mutation altered interaction of NANOS1 with a microRNA biogenesis factor, GEMIN3. The third identified mutation, p.[(Arg246His; Arg276Tyr)], found in the C-terminal RNA-binding domain, was present in a single oligo-astheno-teratozoospermic man. We bioinformatically demonstrated that the p.Arg246His substitution causes a decrease in the positive charge of this domain, potentially altering RNA-binding.

Conclusions This is the first report describing the association of NANOS1 gene mutations with human infertility. Two different infertility phenotypes may reflect distinct functions of N-terminal versus C-terminal regions of NANOS1.