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Functional characterization of novel NR5A1 variants reveals multiple complex roles in disorders of sex development

Variants in the NR5A1 gene encoding SF1 have been described in a diverse spectrum of disorders of sex development (DSD). Recently, we reported the use of a targeted gene panel for DSD where we identified 15 individuals with a variant in NR5A1, nine of which are novel. Here, we examine the functional...

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Autores principales: Robevska, Gorjana, van den Bergen, Jocelyn A., Ohnesorg, Thomas, Eggers, Stefanie, Hanna, Chloe, Hersmus, Remko, Thompson, Elizabeth M., Baxendale, Anne, Verge, Charles F., Lafferty, Antony R., Marzuki, Nanis S., Santosa, Ardy, Listyasari, Nurin A., Riedl, Stefan, Warne, Garry, Looijenga, Leendert, Faradz, Sultana, Ayers, Katie L., Sinclair, Andrew H.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5765430/
https://www.ncbi.nlm.nih.gov/pubmed/29027299
http://dx.doi.org/10.1002/humu.23354
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author Robevska, Gorjana
van den Bergen, Jocelyn A.
Ohnesorg, Thomas
Eggers, Stefanie
Hanna, Chloe
Hersmus, Remko
Thompson, Elizabeth M.
Baxendale, Anne
Verge, Charles F.
Lafferty, Antony R.
Marzuki, Nanis S.
Santosa, Ardy
Listyasari, Nurin A.
Riedl, Stefan
Warne, Garry
Looijenga, Leendert
Faradz, Sultana
Ayers, Katie L.
Sinclair, Andrew H.
author_facet Robevska, Gorjana
van den Bergen, Jocelyn A.
Ohnesorg, Thomas
Eggers, Stefanie
Hanna, Chloe
Hersmus, Remko
Thompson, Elizabeth M.
Baxendale, Anne
Verge, Charles F.
Lafferty, Antony R.
Marzuki, Nanis S.
Santosa, Ardy
Listyasari, Nurin A.
Riedl, Stefan
Warne, Garry
Looijenga, Leendert
Faradz, Sultana
Ayers, Katie L.
Sinclair, Andrew H.
author_sort Robevska, Gorjana
collection PubMed
description Variants in the NR5A1 gene encoding SF1 have been described in a diverse spectrum of disorders of sex development (DSD). Recently, we reported the use of a targeted gene panel for DSD where we identified 15 individuals with a variant in NR5A1, nine of which are novel. Here, we examine the functional effect of these changes in relation to the patient phenotype. All novel variants tested had reduced trans‐activational activity, while several had altered protein level, localization, or conformation. In addition, we found evidence of new roles for SF1 protein domains including a region within the ligand binding domain that appears to contribute to SF1 regulation of Müllerian development. There was little correlation between the severity of the phenotype and the nature of the NR5A1 variant. We report two familial cases of NR5A1 deficiency with evidence of variable expressivity; we also report on individuals with oligogenic inheritance. Finally, we found that the nature of the NR5A1 variant does not inform patient outcomes (including pubertal androgenization and malignancy risk). This study adds nine novel pathogenic NR5A1 variants to the pool of diagnostic variants. It highlights a greater need for understanding the complexity of SF1 function and the additional factors that contribute.
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spelling pubmed-57654302018-02-01 Functional characterization of novel NR5A1 variants reveals multiple complex roles in disorders of sex development Robevska, Gorjana van den Bergen, Jocelyn A. Ohnesorg, Thomas Eggers, Stefanie Hanna, Chloe Hersmus, Remko Thompson, Elizabeth M. Baxendale, Anne Verge, Charles F. Lafferty, Antony R. Marzuki, Nanis S. Santosa, Ardy Listyasari, Nurin A. Riedl, Stefan Warne, Garry Looijenga, Leendert Faradz, Sultana Ayers, Katie L. Sinclair, Andrew H. Hum Mutat Research Articles Variants in the NR5A1 gene encoding SF1 have been described in a diverse spectrum of disorders of sex development (DSD). Recently, we reported the use of a targeted gene panel for DSD where we identified 15 individuals with a variant in NR5A1, nine of which are novel. Here, we examine the functional effect of these changes in relation to the patient phenotype. All novel variants tested had reduced trans‐activational activity, while several had altered protein level, localization, or conformation. In addition, we found evidence of new roles for SF1 protein domains including a region within the ligand binding domain that appears to contribute to SF1 regulation of Müllerian development. There was little correlation between the severity of the phenotype and the nature of the NR5A1 variant. We report two familial cases of NR5A1 deficiency with evidence of variable expressivity; we also report on individuals with oligogenic inheritance. Finally, we found that the nature of the NR5A1 variant does not inform patient outcomes (including pubertal androgenization and malignancy risk). This study adds nine novel pathogenic NR5A1 variants to the pool of diagnostic variants. It highlights a greater need for understanding the complexity of SF1 function and the additional factors that contribute. John Wiley and Sons Inc. 2017-11-02 2018-01 /pmc/articles/PMC5765430/ /pubmed/29027299 http://dx.doi.org/10.1002/humu.23354 Text en © 2017 The Authors. Human Mutation published by Wiley Periodicals, Inc. This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial (http://creativecommons.org/licenses/by-nc/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
spellingShingle Research Articles
Robevska, Gorjana
van den Bergen, Jocelyn A.
Ohnesorg, Thomas
Eggers, Stefanie
Hanna, Chloe
Hersmus, Remko
Thompson, Elizabeth M.
Baxendale, Anne
Verge, Charles F.
Lafferty, Antony R.
Marzuki, Nanis S.
Santosa, Ardy
Listyasari, Nurin A.
Riedl, Stefan
Warne, Garry
Looijenga, Leendert
Faradz, Sultana
Ayers, Katie L.
Sinclair, Andrew H.
Functional characterization of novel NR5A1 variants reveals multiple complex roles in disorders of sex development
title Functional characterization of novel NR5A1 variants reveals multiple complex roles in disorders of sex development
title_full Functional characterization of novel NR5A1 variants reveals multiple complex roles in disorders of sex development
title_fullStr Functional characterization of novel NR5A1 variants reveals multiple complex roles in disorders of sex development
title_full_unstemmed Functional characterization of novel NR5A1 variants reveals multiple complex roles in disorders of sex development
title_short Functional characterization of novel NR5A1 variants reveals multiple complex roles in disorders of sex development
title_sort functional characterization of novel nr5a1 variants reveals multiple complex roles in disorders of sex development
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5765430/
https://www.ncbi.nlm.nih.gov/pubmed/29027299
http://dx.doi.org/10.1002/humu.23354
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