TY - JOUR
T1 - Testis formation in XX individuals resulting from novel pathogenic variants in Wilms' tumor 1 (WT1) gene
AU - Eozenou, Caroline
AU - Gonen, Nitzan
AU - Touzon, Maria Sol
AU - Jorgensen, Anne
AU - Yatsenko, Svetlana A.
AU - Fusee, Leila
AU - Kamel, Alaa K.
AU - Gellen, Balazs
AU - Guercio, Gabriela
AU - Singh, Priti
AU - Witchel, Selma
AU - Berman, Andrea J.
AU - Mainpal, Rana
AU - Totonchi, Mehdi
AU - Meybodi, Anahita Mohseni
AU - Askari, Masomeh
AU - Merel-Chali, Tiphanie
AU - Bignon-Topalovic, Joelle
AU - Migale, Roberta
AU - Costanzo, Mariana
AU - Marino, Roxana
AU - Ramirez, Pablo
AU - Garrido, Natalia Perez
AU - Berensztein, Esperanza
AU - Mekkawy, Mona K.
AU - Schimenti, John C.
AU - Bertalan, Rita
AU - Mazen, Inas
AU - McElreavey, Ken
AU - Belgorosky, Alicia
AU - Lovell-Badge, Robin
AU - Rajkovic, Aleksandar
AU - Bashamboo, Anu
N1 - Publisher Copyright: © 2020 National Academy of Sciences. All rights reserved.
PY - 2020/6/16
Y1 - 2020/6/16
N2 - 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.
AB - 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.
KW - 46,XX TDSD/OTDSD
KW - Organogenesis
KW - Sex determination
KW - WT1
KW - β-CATENIN
UR - http://www.scopus.com/inward/record.url?scp=85086682477&partnerID=8YFLogxK
U2 - https://doi.org/10.1073/pnas.1921676117
DO - https://doi.org/10.1073/pnas.1921676117
M3 - مقالة
C2 - 32493750
SN - 0027-8424
VL - 117
SP - 13680
EP - 13688
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 24
ER -