title: Mutational screening of NR5A1 gene encoding steroidogenic factor 1 in cryptorchidism and male factor infertility and functional analysis of seven undescribed mutations.
abstract: OBJECTIVE
  To study the role of NR5A1 in cryptorchidism and male factor infertility. Mutations in NR5A1 have been initially associated with primary adrenal insufficiency and 46,XY gonadal dysgenesis and more recently with less severe phenotypes, including preliminary descriptions in severe forms of male factor infertility. Far less clear is the possible involvement of NR5A1 mutations in cryptorchidism.
  
  
  METHODS
  Retrospective cross-sectional cohort study and functional analysis of mutant proteins.
  
  
  METHODS
  University department.
  
  
  METHODS
  Nine hundred fifty-nine subjects, including children with cryptorchidism and adults with different semen phenotypes associated or not associated with a history of cryptorchidism.
  
  
  METHODS
  None.
  
  
  METHODS
  Mutation screening of NR5A1 by sequencing all exons. Functional analysis of mutant proteins by transactivation assays of CYP11A1 and CYP17A1 promoters.
  
  
  RESULTS
  We identified seven undescribed and one previously described missense mutation in subjects with severe spermatogenic impairment, without (4/236, 1.7%) and with (3/85, 3.5%) a history of cryptorchidism. Newborns with cryptorchidism carry NR5A1 mutations at low frequency (0.7%), whereas no mutations were found in milder forms of infertility and normozoospermia, irrespective of the presence of cryptorchidism. The mutant proteins showed impaired transactivation of gonadal promoters. A single nucleotide polymorphism (rs1110061; c.437 G→C; p.Gly146Ala) was also associated with more severe forms of spermatogenic impairment with cryptorchidism.
  
  
  CONCLUSIONS
  This study, combined with what is already known about NR5A1-associated phenotypes, suggests considering mutations in this gene as a novel genetic cause of more severe forms of male factor infertility, especially when associated with a history of cryptorchidism.
authors.affiliation: Department of Medicine, Unit of Andrology and Human Reproductive Medicine, University of Padova, Padova, Italy. Electronic address: alberto.ferlin@unipd.it.
authors.forename: Alberto
authors.initials: A
authors.lastname: Ferlin
authors.affiliation: Department of Medicine, Unit of Andrology and Human Reproductive Medicine, University of Padova, Padova, Italy.
authors.forename: Maria Santa
authors.initials: MS
authors.lastname: Rocca
authors.affiliation: Department of Medicine, Unit of Andrology and Human Reproductive Medicine, University of Padova, Padova, Italy.
authors.forename: Cinzia
authors.initials: C
authors.lastname: Vinanzi
authors.affiliation: Department of Medicine, Unit of Andrology and Human Reproductive Medicine, University of Padova, Padova, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Ghezzi
authors.affiliation: Department of Medicine, Unit of Andrology and Human Reproductive Medicine, University of Padova, Padova, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Di Nisio
authors.affiliation: Department of Medicine, Unit of Andrology and Human Reproductive Medicine, University of Padova, Padova, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Foresta
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D002675:Child, Preschool; D015331:Cohort Studies; D003430:Cross-Sectional Studies; D003456:Cryptorchidism / Q000150:complications / Q000175:diagnosis / Q000235:genetics*; D057809:HEK293 Cells; D006801:Humans; D007248:Infertility, Male / Q000150:complications / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed / Q000379:methods; D009154:Mutation / Q000235:genetics*; D012189:Retrospective Studies; D054339:Steroidogenic Factor 1 / Q000235:genetics*
chemical_list: C515057:NR5A1 protein, human; D054339:Steroidogenic Factor 1
keywords: NR5A1; cryptorchidism; male infertility; spermatogenesis; testicular descent