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

Autor:	Eozenou C; Human Developmental Genetics Unit, Institut Pasteur, 75724 Paris, France., Gonen N; Laboratory of Stem Cell Biology and Developmental Genetics, The Francis Crick Institute, NW1 1AT London, United Kingdom.; The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, 5290002 Ramat Gan, Israel., Touzon MS; Endocrinology Department, Research Unit Garrahan Consejo Nacional de Investigaciones Cientificas y Tecnologicas, Hospital de Pediatría Garrahan, Ciudad Autonoma de Buenos Aires 1245, Argentina., Jorgensen A; Department of Growth and Reproduction, Copenhagen University Hospital (Rigshospitalet), 2100 Copenhagen, Denmark., Yatsenko SA; Department of Obstetrics, Gynecology & Reproductive Sciences, Magee-Womens Research Institute, University of Pittsburgh, Pittsburgh, PA 15213.; Department of Pathology, Magee-Womens Research Institute, University of Pittsburgh, Pittsburgh, PA 15213.; Department of Human Genetics, Magee-Womens Research Institute, University of Pittsburgh, Pittsburgh, PA 15213., Fusee L; Human Developmental Genetics Unit, Institut Pasteur, 75724 Paris, France., Kamel AK; Division of Human Genetics and Genome Research, National Research Centre, Dokki, Cairo, 12622, Egypt., Gellen B; Department of Paediatrics, University of Szeged, 6725 Szeged, Hungary., Guercio G; Endocrinology Department, Research Unit Garrahan Consejo Nacional de Investigaciones Cientificas y Tecnologicas, Hospital de Pediatría Garrahan, Ciudad Autonoma de Buenos Aires 1245, Argentina., Singh P; Department of Biomedical Sciences, Cornell University, Ithaca, NY 14853., Witchel S; Department of Pediatrics, University of Pittsburgh Medical Center, Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, PA 15213., Berman AJ; Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA 15213., Mainpal R; Department of Obstetrics, Gynecology & Reproductive Sciences, Magee-Womens Research Institute, University of Pittsburgh, Pittsburgh, PA 15213., Totonchi M; Department of Genetics, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, Academic Center for Education, Culture and Research, 8158968433 Tehran, Iran.; Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, Academic Center for Education, Culture and Research, 8158968433 Tehran, Iran., Mohseni Meybodi A; Department of Genetics, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, Academic Center for Education, Culture and Research, 8158968433 Tehran, Iran., Askari M; Department of Genetics, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, Academic Center for Education, Culture and Research, 8158968433 Tehran, Iran., Merel-Chali T; Human Developmental Genetics Unit, Institut Pasteur, 75724 Paris, France., Bignon-Topalovic J; Human Developmental Genetics Unit, Institut Pasteur, 75724 Paris, France., Migale R; Laboratory of Stem Cell Biology and Developmental Genetics, The Francis Crick Institute, NW1 1AT London, United Kingdom., Costanzo M; Endocrinology Department, Research Unit Garrahan Consejo Nacional de Investigaciones Cientificas y Tecnologicas, Hospital de Pediatría Garrahan, Ciudad Autonoma de Buenos Aires 1245, Argentina., Marino R; Endocrinology Department, Research Unit Garrahan Consejo Nacional de Investigaciones Cientificas y Tecnologicas, Hospital de Pediatría Garrahan, Ciudad Autonoma de Buenos Aires 1245, Argentina., Ramirez P; Endocrinology Department, Research Unit Garrahan Consejo Nacional de Investigaciones Cientificas y Tecnologicas, Hospital de Pediatría Garrahan, Ciudad Autonoma de Buenos Aires 1245, Argentina., Perez Garrido N; Endocrinology Department, Research Unit Garrahan Consejo Nacional de Investigaciones Cientificas y Tecnologicas, Hospital de Pediatría Garrahan, Ciudad Autonoma de Buenos Aires 1245, Argentina., Berensztein E; Endocrinology Department, Research Unit Garrahan Consejo Nacional de Investigaciones Cientificas y Tecnologicas, Hospital de Pediatría Garrahan, Ciudad Autonoma de Buenos Aires 1245, Argentina., Mekkawy MK; Division of Human Genetics and Genome Research, National Research Centre, Dokki, Cairo, 12622, Egypt., Schimenti JC; Department of Biomedical Sciences, Cornell University, Ithaca, NY 14853., Bertalan R; 1st Department of Pediatrics, Semmelweis University, 1083 Budapest, Hungary., Mazen I; Division of Human Genetics and Genome Research, National Research Centre, Dokki, Cairo, 12622, Egypt., McElreavey K; Human Developmental Genetics Unit, Institut Pasteur, 75724 Paris, France., Belgorosky A; Endocrinology Department, Research Unit Garrahan Consejo Nacional de Investigaciones Cientificas y Tecnologicas, Hospital de Pediatría Garrahan, Ciudad Autonoma de Buenos Aires 1245, Argentina., Lovell-Badge R; Laboratory of Stem Cell Biology and Developmental Genetics, The Francis Crick Institute, NW1 1AT London, United Kingdom., Rajkovic A; Department of Pathology, Obstetrics, Gynecology and Reproductive Sciences, University of California, San Francisco, CA 94158., Bashamboo A; Human Developmental Genetics Unit, Institut Pasteur, 75724 Paris, France; anu.bashamboo@pasteur.fr.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2020 Jun 16; Vol. 117 (24), pp. 13680-13688. Date of Electronic Publication: 2020 Jun 03.
DOI:	10.1073/pnas.1921676117
Abstrakt:	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. Competing Interests: The authors declare no competing interest. (Copyright © 2020 the Author(s). Published by PNAS.)
Databáze:	MEDLINE
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