Testis formation in XX individuals resulting from novel pathogenic variants in Wilms' tumor 1 (WT1) gene

Caroline Eozenou, Nitzan Gonen, Maria Sol Touzon, Anne Jorgensen, Svetlana A. Yatsenko, Leila Fusee, Alaa K. Kamel, Balazs Gellen, Gabriela Guercio, Priti Singh, Selma Witchel, Andrea J. Berman, Rana Mainpal, Mehdi Totonchi, Anahita Mohseni Meybodi, Masomeh Askari, Tiphanie Merel-Chali, Joelle Bignon-Topalovic, Roberta Migale, Mariana CostanzoRoxana Marino, Pablo Ramirez, Natalia Perez Garrido, Esperanza Berensztein, Mona K. Mekkawy, John C. Schimenti, Rita Bertalan, Inas Mazen, Ken McElreavey, Alicia Belgorosky, Robin Lovell-Badge, Aleksandar Rajkovic, Anu Bashamboo

Research output: Contribution to journalArticlepeer-review

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 × 10-6), and the incidence of WT1 variants in 46,XX DSD is enriched compared to control populations (P < 1.8 × 10-4). The introduction of ZF4 mutants into a human granulosa cell line resulted in up-regulation of endogenous Sertoli cell transcripts and Wt1Arg495Gly/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 β-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.

Original languageEnglish
Pages (from-to)13680-13688
Number of pages9
JournalProceedings of the National Academy of Sciences of the United States of America
Volume117
Issue number24
DOIs
StatePublished - 16 Jun 2020

Keywords

  • 46,XX TDSD/OTDSD
  • Organogenesis
  • Sex determination
  • WT1
  • β-CATENIN

All Science Journal Classification (ASJC) codes

  • General

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