AUTHOR=Gau Maki , Suga Ryota , Hijikata Atsushi , Kashimada Ayako , Takagi Masatoshi , Nakagawa Ryuichi , Takasawa Kei , Shirai Tsuyoshi , Kashimada Kenichi , Morio Tomohiro TITLE=A novel variant of NR5A1, p.R350W implicates potential interactions with unknown co-factors or ligands JOURNAL=Frontiers in Endocrinology VOLUME=13 YEAR=2023 URL=https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2022.1033074 DOI=10.3389/fendo.2022.1033074 ISSN=1664-2392 ABSTRACT=Introduction

NR5A1 and NR5A2 belong to an orphan nuclear receptor group, and approximately 60% of their amino acid sequences are conserved. Transcriptional regulation of NR5A receptors depends on interactions with co-factors or unidentified ligands.

Purpose and methods

We employed in vitro and in silico analysis for elucidating the pathophysiology of a novel variant in the ligand-binding domain of NR5A1, p.R350W which was identified from a 46,XY patient with atypical genitalia.

Results

In the study, [1] reporter assays demonstrated that R350 is essential for NR5A1; [2] 3D model analysis predicted that R350 interacted with endogenous ligands or unknown cofactors rather than stabilizing the structure; [3] R350 is not conserved in NR5A2 but is specifically required for NR5A1; and [4] none of the 22 known missense variants of the ligand binding domain satisfied all the previous conditions [1]-[3], suggesting the unique role of R350 in NR5A1.

Conclusion

Our data suggest that NR5A1 has unidentified endogenous ligands or co-activators that selectively potentiate the transcriptional function of NR5A1 in vivo.