Testis formation in XX individuals resulting from novel pathogenic variants in Wilms' tumor 1 (WT1) gene
Open Access
- 16 June 2020
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 117 (24), 13680-13688
- https://doi.org/10.1073/pnas.1921676117
Abstract
Sex determination in mammals is governed by antagonistic interactions of two genetic pathways, imbalance in which may lead to disorders/differences of sex development (DSD) in human. Among 46,XX individuals with testicular DSD (TDSD) or ovotesticular DSD (OTDSD), testicular tissue is present in the gonad. Although the testis-determining gene SRY is present in many cases, the etiology is unknown in most SRY-negative patients. We performed exome sequencing on 78 individuals with 46,XX TDSD/OTDSD of unknown genetic etiology and identified seven (8.97%) with heterozygous variants affecting the fourth zinc finger (ZF4) of Wilms' tumor 1 (WT1) (p.Ser478Thrfs*17, p.Pro481Leufs*15, p.Lys491Glu, p.Arg495Gln [x3], p.Arg495Gly). The variants were de novo in six families (P = 4.4 x 10(-6)), and the incidence of WT1 variants in 46,XX DSD is enriched compared to control populations (P < 1.8 x 10(-4)). The introduction of ZF4 mutants into a human granulosa cell line resulted in up-regulation of endogenous Sertoli cell transcripts and Wt1(Arg495Gly/Arg495Gly) XX mice display masculinization of the fetal gonads. The phenotype could be explained by the ability of the mutated proteins to physically interact with and sequester a key pro-ovary factor beta-CATENIN, which may lead to up-regulation of testis-specific pathway. Our data show that unlike previous association of WT1 and 46,XY DSD, ZF4 variants of WT1 are a relatively common cause of 46,XX TDSD/OTDSD. This expands the spectrum of phenotypes associated with WT1 variants and shows that the WT1 protein affecting ZF4 can function as a protestis factor in an XX chromosomal context.Funding Information
- European Society for Paediatric Endocrinology (-)
- Agence Nationale de la Recherche (ANR-10-LABX-73 REVIVE)
- Agence Nationale de la Recherche (ANR-17-CE14-0038-01)
- European Union (COST Action DSDnet BM1303)
- Cancer Research UK (FC001107)
- RCUK | Medical Research Council (FC001107)
- Wellcome (FC001107)
- MINCyT | ANPCyT | Fondo para la Investigación Científica y Tecnológica (PIDC-20160028)
- MINCyT | Agencia Nacional de Promoción Científica y Tecnológica (PICT-2013-0181y PICT2016-0214)
- Consejo Nacional de Investigaciones Científicas y Técnicas (_)
- National Institute of Health, USA (R01HD070647)
- National Institute of Health, USA (R21HD074278)
- Danish Government (EDMaRC programme)
- National Institute of Health, USA (GM116889)
- American Cancer Society (RSG-17-1.97-01-RMC)
This publication has 39 references indexed in Scilit:
- Mammalian sex determination—insights from humans and miceChromosome Research, 2012
- Identification of SOX3 as an XX male sex reversal gene in mice and humansJCI Insight, 2011
- To β or not to β: Canonical β‐catenin signaling pathway and ovarian developmentDevelopmental Dynamics, 2008
- Stabilization of β-catenin in XY gonads causes male-to-female sex-reversalHuman Molecular Genetics, 2008
- Activation of -catenin signaling by Rspo1 controls differentiation of the mammalian ovaryHuman Molecular Genetics, 2008
- WT1 mutations in Meacham syndrome suggest a coelomic mesothelial origin of the cardiac and diaphragmatic malformationsAmerican Journal of Medical Genetics Part A, 2007
- R-spondin1 is essential in sex determination, skin differentiation and malignancyNature Genetics, 2006
- 46,XX sex reversal with partial duplication of chromosome arm 22qAmerican Journal of Medical Genetics Part A, 2004
- Identification of Constitutional WT1 Mutations, in Patients with Isolated Diffuse Mesangial Sclerosis, and Analysis of Genotype/Phenotype Correlations by Use of a Computerized Mutation DatabaseAmerican Journal of Human Genetics, 1998
- Germline mutations in the Wilms' tumor suppressor gene are associated with abnormal urogenital development in Denys-Drash syndromeCell, 1991