title: The mutational spectrum of WT1 in male infertility.
abstract: OBJECTIVE
  We evaluated the impact of WT1 mutations in isolated severe spermatogenic impairment in a population of European ancestry. WT1 was first identified as the gene responsible for Wilms tumor. It was later associated with a plethora of clinical phenotypes often accompanied by urogenital defects and male infertility. The recent finding of WT1 missense mutations in Chinese azoospermic males without major gonadal malformations broadened the phenotypic spectrum of WT1 defects and motivated this study.
  
  
  METHODS
  We analyzed the WT1 coding region in a cohort of 194 Portuguese patients with nonobstructive azoospermia and in 188 with severe oligozoospermia with increased depth for the exons encoding the regulatory region of the protein. We also analyzed a group of 31 infertile males with a clinical history of unilateral or bilateral cryptorchidism and 1 patient with anorchia.
  
  
  RESULTS
  We found 2 WT1 missense substitutions at higher frequency in patients than in controls. 1) A novel variant in exon 1 (p.Pro130Leu) that disrupted a mammalian specific polyproline stretch in the self-association domain was more frequent in azoospermia cases (0.27% vs 0.13%, p = 0.549). 2) A rare variant in a conserved residue in close proximity to the first zinc finger (pCys350Arg) was more frequent in severe oligozoospermia cases (0.80% vs 0.13%, p = 0.113).
  
  
  CONCLUSIONS
  Results suggest a role for rare WT1 damaging variants in severe spermatogenic failure in populations of European ancestry. Large multicenter studies are needed to fully assess the contribution of WT1 genetic alterations to male infertility in the absence of other disease phenotypes.
authors.affiliation: Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal; Health Sciences Autonomous Section, University of Aveiro, Aveiro, Portugal.
authors.forename: Catarina M
authors.initials: CM
authors.lastname: Seabra
authors.affiliation: Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal.
authors.forename: Sofia
authors.initials: S
authors.lastname: Quental
authors.affiliation: Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal; Graduate Program in Areas of Basic and Applied Biology, University of Porto, Porto, Portugal; Abel Salazar Institute of Biomedical Sciences, University of Porto, Porto, Portugal; Department of Genetics, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Ana C
authors.initials: AC
authors.lastname: Lima
authors.affiliation: Department of Genetics, Faculty of Medicine, University of Porto, Porto, Portugal.
authors.forename: Filipa
authors.initials: F
authors.lastname: Carvalho
authors.affiliation: Department of Human Genetics, National Institute of Health Dr. Ricardo Jorge, Lisboa, Portugal.
authors.forename: João
authors.initials: J
authors.lastname: Gonçalves
authors.affiliation: Department of Genetics, Faculty of Medicine, University of Porto, Porto, Portugal.
authors.forename: Susana
authors.initials: S
authors.lastname: Fernandes
authors.affiliation: Department of Human Genetics, National Institute of Health Dr. Ricardo Jorge, Lisboa, Portugal.
authors.forename: Iris
authors.initials: I
authors.lastname: Pereira
authors.affiliation: Department of Human Genetics, National Institute of Health Dr. Ricardo Jorge, Lisboa, Portugal.
authors.forename: Júlia
authors.initials: J
authors.lastname: Silva
authors.affiliation: Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal; Abel Salazar Institute of Biomedical Sciences, University of Porto, Porto, Portugal.
authors.forename: Patrícia I
authors.initials: PI
authors.lastname: Marques
authors.affiliation: Laboratory of Cell Biology, Unit for Multidisciplinary Research in Biomedicine, University of Porto, Porto, Portugal.
authors.forename: Mário
authors.initials: M
authors.lastname: Sousa
authors.affiliation: Department of Genetics, Faculty of Medicine, University of Porto, Porto, Portugal.
authors.forename: Alberto
authors.initials: A
authors.lastname: Barros
authors.affiliation: Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal.
authors.forename: Susana
authors.initials: S
authors.lastname: Seixas
authors.affiliation: Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal; Faculty of Sciences, University of Porto, Porto, Portugal.
authors.forename: António
authors.initials: A
authors.lastname: Amorim
authors.affiliation: Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal. Electronic address: alopes@ipatimup.pt.
authors.forename: Alexandra M
authors.initials: AM
authors.lastname: Lopes
mesh_terms: D004252:DNA Mutational Analysis; D016162:Genes, Wilms Tumor; D006801:Humans; D007248:Infertility, Male / Q000235:genetics*; D008297:Male; D009154:Mutation; D025721:WT1 Proteins / Q000235:genetics*
chemical_list: D025721:WT1 Proteins; C583751:WT1 protein, human
keywords: European continental ancestry group; Wilms tumor; genes; infertility; male; mutation; testis