Testis formation in XX individuals resulting from novel pathogenic variants in Wilms’ tumor 1 ( <i>WT1</i> ) gene
Caroline Eozénou, Nitzan Gonen, María Sol Touzón, Anne Jørgensen, Svetlana A. Yatsenko, Leila Fusée, Alaa K. Kamel, Balázs Gellén, Gabriela Guercio, Priti Singh, Selma F. Witchel, Andrea J. Berman, Mainpal Rana, Mehdi Totonchi, Anahita Mohseni Meybodi, Masomeh Askari, Tiphanie Merel-Chali, Joëlle Bignon‐Topalovic, Roberta Migale, Mariana Costanzo, Roxana Marino, Pablo Ramírez, Natalia Pérez Garrido, Esperanza Berensztein, Mona K. Mekkawy, John C. Schimenti, Rita Bertalan, Inas Mazen, Ken McElreavey, Alicia Belgorosky, Robin Lovell‐Badge, Aleksandar Rajkovic, Anu Bashamboo
Abstract
Significance Sex development involves a precise spatiotemporal expression and interactions of numerous genetic factors, including the WT1 (Wilms tumor 1) gene. Complete and partial loss-of-function WT1 variants are associated with 46,XY disorders/differences of sex development (DSD). Some 46,XX individuals develop testis in absence of the testis-determining gene SRY . We describe a genotype/phenotype association where variants impacting the C-terminal zinc finger (ZF4) of WT1 cause testis development in 46,XX individuals. XX mice carrying a pathogenic variant of ZF4 display masculinization of the fetal gonads. Testis formation may be due to inappropriate interaction between the mutated WT1 and an essential ovarian determinant β-CATENIN. These data show that variants affecting a specific domain of a developmental transcription factor can switch organ fate.