title: 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.
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.
authors: Polish Academy of Sciences, Institute of Human Genetics, Strzeszyńska 32, Poznań 60-479, Poland.
authors: Kamila
authors: K
authors: Kusz-Zamelczyk
authors: Marcin
authors: M
authors: Sajek
authors: Anna
authors: A
authors: Spik
authors: Renata
authors: R
authors: Glazar
authors: Piotr
authors: P
authors: Jędrzejczak
authors: Anna
authors: A
authors: Latos-Bieleńska
authors: Maciej
authors: M
authors: Kotecki
authors: Leszek
authors: L
authors: Pawelczyk
authors: Jadwiga
authors: J
authors: Jaruzelska
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D053713:Azoospermia / Q000235:genetics* / Q000473:pathology; D006801:Humans; D008297:Male; D051379:Mice; D008958:Models, Molecular; D058977:Molecular Sequence Annotation; D008969:Molecular Sequence Data; D009154:Mutation; D009845:Oligospermia / Q000235:genetics* / Q000473:pathology; D010375:Pedigree; D010802:Phylogeny; D018807:Polymorphism, Single-Stranded Conformational; D016601:RNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D017422:Sequence Analysis, DNA; D013737:Testis / Q000166:cytology / Q000473:pathology*
chemical_list: C515170:NANOS1 protein, human; D016601:RNA-Binding Proteins