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

Caroline EozenouNitzan GonenMaria Sol TouzonAnne JorgensenSvetlana A YatsenkoLeila FuseeAlaa K KamelBalazs GellenGabriela GuercioPriti SinghSelma WitchelAndrea J BermanMainpal RanaMehdi TotonchiAnahita Mohseni MeybodiMasomeh AskariTiphanie Merel-ChaliJoelle Bignon-TopalovicRoberta MigaleMariana CostanzoRoxana MarinoPablo RamirezNatalia Perez GarridoEsperanza BerenszteinMona K MekkawyJohn C SchimentiRita BertalanInas MazenKen McElreaveyAlicia BelgoroskyRobin Lovell-BadgeAleksandar RajkovicAnu Bashamboo
Published in: Proceedings of the National Academy of Sciences of the United States of America (2020)
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 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 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.
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