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dc.contributor.author
Eozenou, Caroline
dc.contributor.author
Gonen, Nitzan
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Touzon, María Sol
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Jorgensen, Anne
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Yatsenko, Svetlana A.
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Fusee, Leila
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Kamel, Alaa K.
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Gellen, Balazs
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Guercio, Gabriela Viviana
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Singh, Priti
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Witchel, Selma
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Berman, Andrea J.
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Mainpal, Rana
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Totonchi, Mehdi
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Mohseni Meybodi, Anahita
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Askari, Masomeh
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Merel-Chali, Tiphanie
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Bignon Topalovic, Joelle
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Migale, Roberta
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Costanzo, Mariana
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Marino, Roxana Marcela
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Ramirez, Pablo
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Perez Garrido, Natalia Isabel
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Berensztein, Esperanza Beatriz
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Mekkawy, Mona K.
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Schimenti, John C.
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Bertalan, Rita
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Mazen, Inas
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McElreavey, Ken
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Belgorosky, Alicia
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Lovell Badge, Robin
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Rajkovic, Aleksandar
dc.contributor.author
Bashamboo, Anu
dc.date.available
2022-10-11T19:29:38Z
dc.date.issued
2020-06
dc.identifier.citation
Eozenou, Caroline; Gonen, Nitzan; Touzon, María Sol; Jorgensen, Anne; Yatsenko, Svetlana A.; et al.; Testis formation in XX individuals resulting from novel pathogenic variants in Wilms' tumor 1 (WT1) gene; National Academy of Sciences; Proceedings of the National Academy of Sciences of The United States of America; 117; 24; 6-2020; 13680-13688
dc.identifier.issn
0027-8424
dc.identifier.uri
http://hdl.handle.net/11336/172568
dc.description.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.
dc.format
application/pdf
dc.language.iso
eng
dc.publisher
National Academy of Sciences
dc.rights
info:eu-repo/semantics/openAccess
dc.rights.uri
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
dc.subject
46,XX TDSD/OTDSD
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ORGANOGENESIS
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SEX DETERMINATION
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WT1
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Β-CATENIN
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Endocrinología y Metabolismo
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Medicina Clínica
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CIENCIAS MÉDICAS Y DE LA SALUD
dc.title
Testis formation in XX individuals resulting from novel pathogenic variants in Wilms' tumor 1 (WT1) gene
dc.type
info:eu-repo/semantics/article
dc.type
info:ar-repo/semantics/artículo
dc.type
info:eu-repo/semantics/publishedVersion
dc.date.updated
2022-09-15T02:18:26Z
dc.journal.volume
117
dc.journal.number
24
dc.journal.pagination
13680-13688
dc.journal.pais
Estados Unidos
dc.journal.ciudad
Washington D.C
dc.description.fil
Fil: Eozenou, Caroline. Institut Pasteur de Paris.; Francia
dc.description.fil
Fil: Gonen, Nitzan. The Francis Crick Institute; Reino Unido. Bar-ilan University; Israel
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Fil: Touzon, María Sol. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina
dc.description.fil
Fil: Jorgensen, Anne. Universidad de Copenhagen; Dinamarca
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Fil: Yatsenko, Svetlana A.. University of Pittsburgh; Estados Unidos
dc.description.fil
Fil: Fusee, Leila. Institut Pasteur de Paris.; Francia
dc.description.fil
Fil: Kamel, Alaa K.. National Research Centre; Egipto
dc.description.fil
Fil: Gellen, Balazs. University Of Szeged; Hungría
dc.description.fil
Fil: Guercio, Gabriela Viviana. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina
dc.description.fil
Fil: Singh, Priti. Cornell University; Estados Unidos
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Fil: Witchel, Selma. University of Pittsburgh; Estados Unidos
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Fil: Berman, Andrea J.. University of Pittsburgh; Estados Unidos
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Fil: Mainpal, Rana. University of Pittsburgh; Estados Unidos
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Fil: Totonchi, Mehdi. Academic Center for Education, Culture and Research; Irán
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Fil: Mohseni Meybodi, Anahita. Academic Center for Education, Culture and Research; Irán
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Fil: Askari, Masomeh. Academic Center for Education, Culture and Research; Irán
dc.description.fil
Fil: Merel-Chali, Tiphanie. Institut Pasteur de Paris.; Francia
dc.description.fil
Fil: Bignon Topalovic, Joelle. Institut Pasteur de Paris.; Francia
dc.description.fil
Fil: Migale, Roberta. The Francis Crick Institute; Reino Unido
dc.description.fil
Fil: Costanzo, Mariana. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina
dc.description.fil
Fil: Marino, Roxana Marcela. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina
dc.description.fil
Fil: Ramirez, Pablo. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina
dc.description.fil
Fil: Perez Garrido, Natalia Isabel. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina
dc.description.fil
Fil: Berensztein, Esperanza Beatriz. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina
dc.description.fil
Fil: Mekkawy, Mona K.. National Research Centre; Egipto
dc.description.fil
Fil: Schimenti, John C.. Cornell University; Estados Unidos
dc.description.fil
Fil: Bertalan, Rita. Semmelweis University; Hungría
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Fil: Mazen, Inas. National Research Centre; Egipto
dc.description.fil
Fil: McElreavey, Ken. Institut Pasteur de Paris.; Francia
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Fil: Belgorosky, Alicia. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina
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Fil: Lovell Badge, Robin. The Francis Crick Institute; Reino Unido
dc.description.fil
Fil: Rajkovic, Aleksandar. University of California; Estados Unidos
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Fil: Bashamboo, Anu. Institut Pasteur de Paris.; Francia
dc.journal.title
Proceedings of the National Academy of Sciences of The United States of America
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/url/http://www.pnas.org/lookup/doi/10.1073/pnas.1921676117
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/doi/http://dx.doi.org/10.1073/pnas.1921676117
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