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NR5A1 is a novel disease gene for 46,XX testicular and ovotesticular disorders of sex development

PURPOSE: We aimed to identify the genetic cause in a cohort of 11 unrelated cases and two sisters with 46,XX SRY-negative (ovo)testicular disorders of sex development (DSD). METHODS: Whole-exome sequencing (n = 9), targeted resequencing (n = 4), and haplotyping were performed. Immunohistochemistry o...

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Autores principales: Baetens, Dorien, Stoop, Hans, Peelman, Frank, Todeschini, Anne-Laure, Rosseel, Toon, Coppieters, Frauke, Veitia, Reiner A., Looijenga, Leendert H.J., De Baere, Elfride, Cools, Martine
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5392598/
https://www.ncbi.nlm.nih.gov/pubmed/27490115
http://dx.doi.org/10.1038/gim.2016.118
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author Baetens, Dorien
Stoop, Hans
Peelman, Frank
Todeschini, Anne-Laure
Rosseel, Toon
Coppieters, Frauke
Veitia, Reiner A.
Looijenga, Leendert H.J.
De Baere, Elfride
Cools, Martine
author_facet Baetens, Dorien
Stoop, Hans
Peelman, Frank
Todeschini, Anne-Laure
Rosseel, Toon
Coppieters, Frauke
Veitia, Reiner A.
Looijenga, Leendert H.J.
De Baere, Elfride
Cools, Martine
author_sort Baetens, Dorien
collection PubMed
description PURPOSE: We aimed to identify the genetic cause in a cohort of 11 unrelated cases and two sisters with 46,XX SRY-negative (ovo)testicular disorders of sex development (DSD). METHODS: Whole-exome sequencing (n = 9), targeted resequencing (n = 4), and haplotyping were performed. Immunohistochemistry of sex-specific markers was performed on patients' gonads. The consequences of mutation were investigated using luciferase assays, localization studies, and RNA-seq. RESULTS: We identified a novel heterozygous NR5A1 mutation, c.274C>T p.(Arg92Trp), in three unrelated patients. The Arg92 residue is highly conserved and located in the Ftz-F1 region, probably involved in DNA-binding specificity and stability. There were no consistent changes in transcriptional activation or subcellular localization. Transcriptomics in patient-derived lymphocytes showed upregulation of MAMLD1, a direct NR5A1 target previously associated with 46,XY DSD. In gonads of affected individuals, ovarian FOXL2 and testicular SRY-independent SOX9 expression observed. CONCLUSIONS: We propose NR5A1, previously associated with 46,XY DSD and 46,XX primary ovarian insufficiency, as a novel gene for 46,XX (ovo)testicular DSD. We hypothesize that p.(Arg92Trp) results in decreased inhibition of the male developmental pathway through downregulation of female antitestis genes, thereby tipping the balance toward testicular differentiation in 46,XX individuals. In conclusion, our study supports a role for NR5A1 in testis differentiation in the XX gonad. Genet Med 19 4, 367–376.
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spelling pubmed-53925982017-05-01 NR5A1 is a novel disease gene for 46,XX testicular and ovotesticular disorders of sex development Baetens, Dorien Stoop, Hans Peelman, Frank Todeschini, Anne-Laure Rosseel, Toon Coppieters, Frauke Veitia, Reiner A. Looijenga, Leendert H.J. De Baere, Elfride Cools, Martine Genet Med Original Research Article PURPOSE: We aimed to identify the genetic cause in a cohort of 11 unrelated cases and two sisters with 46,XX SRY-negative (ovo)testicular disorders of sex development (DSD). METHODS: Whole-exome sequencing (n = 9), targeted resequencing (n = 4), and haplotyping were performed. Immunohistochemistry of sex-specific markers was performed on patients' gonads. The consequences of mutation were investigated using luciferase assays, localization studies, and RNA-seq. RESULTS: We identified a novel heterozygous NR5A1 mutation, c.274C>T p.(Arg92Trp), in three unrelated patients. The Arg92 residue is highly conserved and located in the Ftz-F1 region, probably involved in DNA-binding specificity and stability. There were no consistent changes in transcriptional activation or subcellular localization. Transcriptomics in patient-derived lymphocytes showed upregulation of MAMLD1, a direct NR5A1 target previously associated with 46,XY DSD. In gonads of affected individuals, ovarian FOXL2 and testicular SRY-independent SOX9 expression observed. CONCLUSIONS: We propose NR5A1, previously associated with 46,XY DSD and 46,XX primary ovarian insufficiency, as a novel gene for 46,XX (ovo)testicular DSD. We hypothesize that p.(Arg92Trp) results in decreased inhibition of the male developmental pathway through downregulation of female antitestis genes, thereby tipping the balance toward testicular differentiation in 46,XX individuals. In conclusion, our study supports a role for NR5A1 in testis differentiation in the XX gonad. Genet Med 19 4, 367–376. Nature Publishing Group 2017-04 2016-08-04 /pmc/articles/PMC5392598/ /pubmed/27490115 http://dx.doi.org/10.1038/gim.2016.118 Text en Copyright © 2016 The Author(s) http://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/
spellingShingle Original Research Article
Baetens, Dorien
Stoop, Hans
Peelman, Frank
Todeschini, Anne-Laure
Rosseel, Toon
Coppieters, Frauke
Veitia, Reiner A.
Looijenga, Leendert H.J.
De Baere, Elfride
Cools, Martine
NR5A1 is a novel disease gene for 46,XX testicular and ovotesticular disorders of sex development
title NR5A1 is a novel disease gene for 46,XX testicular and ovotesticular disorders of sex development
title_full NR5A1 is a novel disease gene for 46,XX testicular and ovotesticular disorders of sex development
title_fullStr NR5A1 is a novel disease gene for 46,XX testicular and ovotesticular disorders of sex development
title_full_unstemmed NR5A1 is a novel disease gene for 46,XX testicular and ovotesticular disorders of sex development
title_short NR5A1 is a novel disease gene for 46,XX testicular and ovotesticular disorders of sex development
title_sort nr5a1 is a novel disease gene for 46,xx testicular and ovotesticular disorders of sex development
topic Original Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5392598/
https://www.ncbi.nlm.nih.gov/pubmed/27490115
http://dx.doi.org/10.1038/gim.2016.118
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