Testis formation in XX individuals resulting from novel pathogenic variants in Wilms’ tumor 1 (WT1) gene
journal contributionposted on 01.07.2020, 11:53 by 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 Costanzo, Roxana 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
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.