Please use this identifier to cite or link to this item: https://hdl.handle.net/2440/113447
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Type: Journal article
Title: Functional characterization of novel NR5A1 variants reveals multiple complex roles in disorders of sex development
Author: Robevska, G.
van den Bergen, J.
Ohnesorg, T.
Eggers, S.
Hanna, C.
Hersmus, R.
Thompson, E.
Baxendale, A.
Verge, C.
Lafferty, A.
Marzuki, N.
Santosa, A.
Listyasari, N.
Riedl, S.
Warne, G.
Looijenga, L.
Faradz, S.
Ayers, K.
Sinclair, A.
Citation: Human Mutation, 2018; 39(1):124-139
Publisher: Wiley
Issue Date: 2018
ISSN: 1059-7794
1098-1004
Statement of
Responsibility: 
Gorjana Robevska, Jocelyn A. van den Bergen, Thomas Ohnesorg, Stefanie Eggers, Chloe Hanna, Remko Hersmus, Elizabeth M. Thompson, Anne Baxendale, Charles F. Verge, Antony R. Lafferty, Nanis S. Marzuki, Ardy Santosa, Nurin A. Listyasari, Stefan Riedl, Garry Warne, Leendert Looijenga, Sultana Faradz, Katie L. Ayers, Andrew H. Sinclair
Abstract: 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.
Keywords: Disorders of sex development
Genotype-phenotype correlation
Mutation
NR5A1
Oligogenic
Variable expressivity
Rights: This is an open access article under the terms of the Creative Commons Attribution-Non Commercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. Copyright 2017 The Authors. Human Mutation published by Wiley Periodicals, Inc.
DOI: 10.1002/humu.23354
Grant ID: http://purl.org/au-research/grants/nhmrc/546517
NHMRC
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