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

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.

DOI: 10.1002/humu.23354

Cite this paper

@article{Robevska2017FunctionalCO, title={Functional characterization of novel NR5A1 variants reveals multiple complex roles in disorders of sex development.}, author={Gorjana Robevska and Jocelyn A. van den Bergen and T Ohnesorg and Stefanie Eggers and Chloe Hanna and Remko Hersmus and Elizabeth M. Thompson and Anne Baxendale and Charles F Verge and Antony Richard Lafferty and Nanis Sacharina Marzuki and Ardy Santosa and Nurin Aisyiyah Listyasari and Stefan W Riedl and Garry L. Warne and Leendert H. J. Looijenga and Sultana M. H. Faradz and Katie L Ayers and Andrew H. Sinclair}, journal={Human mutation}, year={2017} }