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

Proc Natl Acad Sci U S A. 2020 Jun 16;117(24):13680-13688. doi: 10.1073/pnas.1921676117. Epub 2020 Jun 3.

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.

Keywords: 46,XX TDSD/OTDSD; WT1; organogenesis; sex determination; β-CATENIN.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 46, XX Testicular Disorders of Sex Development / genetics
  • 46, XX Testicular Disorders of Sex Development / metabolism*
  • 46, XX Testicular Disorders of Sex Development / pathology
  • Animals
  • Child, Preschool
  • Female
  • Humans
  • Infant
  • Male
  • Mice
  • Ovary / growth & development
  • Ovary / metabolism
  • Testis / growth & development
  • Testis / metabolism*
  • Testis / pathology
  • WT1 Proteins / chemistry
  • WT1 Proteins / genetics
  • WT1 Proteins / metabolism*
  • Zinc Fingers
  • beta Catenin / genetics
  • beta Catenin / metabolism

Substances

  • WT1 Proteins
  • WT1 protein, human
  • WT1 protein, mouse
  • beta Catenin