• PMID: 25451826
• Gene Name: WT1
• Condition: Male infertility,
• Association: The study 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 azoosperm
• Mutation: p.Pro130Leu, pCys350Arg
• Population size: 414
• Population details: 414 (194 patients with nonobstructive azoospermia, 188 with severe oligozoospermia, 31 infertile males, 1 patient with anorchia)
• Sex: Male
• Infertility type: Male infertility
• Other associated phenotypes: Male infertility

The mutational spectrum of WT1 in male infertility

Seabra CM, Quental S, Lima AC, Carvalho F, Gonçalves J, Fernandes S, Pereira I, Silva J, Marques PI, Sousa M, Barros A, Seixas S, Amorim A, Lopes AM.

PURPOSE: 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. MATERIALS AND 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. CI - Copyright © 2015 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved. FAU - Seabra, Catarina M AU - Seabra CM AD - Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal; Health Sciences Autonomous Section, University of Aveiro, Aveiro, Portugal. FAU - Quental, Sofia AU - Quental S AD - Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal. FAU - Lima, Ana C AU - Lima AC AD - 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. FAU - Carvalho, Filipa AU - Carvalho F AD - Department of Genetics, Faculty of Medicine, University of Porto, Porto, Portugal. FAU - Gonçalves, João AU - Gonçalves J AD - Department of Human Genetics, National Institute of Health Dr. Ricardo Jorge, Lisboa, Portugal. FAU - Fernandes, Susana AU - Fernandes S AD - Department of Genetics, Faculty of Medicine, University of Porto, Porto, Portugal. FAU - Pereira, Iris AU - Pereira I AD - Department of Human Genetics, National Institute of Health Dr. Ricardo Jorge, Lisboa, Portugal. FAU - Silva, Júlia AU - Silva J AD - Department of Human Genetics, National Institute of Health Dr. Ricardo Jorge, Lisboa, Portugal. FAU - Marques, Patrícia I AU - Marques PI AD - Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal; Abel Salazar Institute of Biomedical Sciences, University of Porto, Porto, Portugal. FAU - Sousa, Mário AU - Sousa M AD - Laboratory of Cell Biology, Unit for Multidisciplinary Research in Biomedicine, University of Porto, Porto, Portugal. FAU - Barros, Alberto AU - Barros A AD - Department of Genetics, Faculty of Medicine, University of Porto, Porto, Portugal. FAU - Seixas, Susana AU - Seixas S AD - Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal. FAU - Amorim, António AU - Amorim A AD - Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal; Faculty of Sciences, University of Porto, Porto, Portugal.