NR5A1/SF-1 Collaborates with Inhibin α and the Androgen Receptor

Steroidogenic factor 1 (SF-1) is a nuclear receptor that regulates steroidogenesis and reproductive development. <i>NR5A1</i>/SF-1 variants are associated with a broad spectrum of phenotypes across individuals with disorders of sex development (DSDs). Oligogenic inheritance has been suggested as an explanation. SF-1 interacts with numerous partners. Here, we investigated a constellation of gene variants identified in a 46,XY severely undervirilized individual carrying an ACMG-categorized 'pathogenic' <i>NR5A1</i>/SF-1 variant in comparison to the healthy carrier father. Candidate genes were revealed by whole exome sequencing, and pathogenicity was predicted by different in silico tools. We found variants in <i>NR1H2</i> and <i>INHA</i> associated with steroidogenesis, sex development, and reproduction. The identified variants were tested in cell models. Novel SF-1 and NR1H2 binding sites in the <i>AR</i> and <i>INHA</i> gene promoters were found. Transactivation studies showed that wild-type <i>NR5A1</i>/SF-1 regulates <i>INHA</i> and <i>AR</i> gene expression, while the <i>NR5A1</i>/SF-1 variant had decreased transcriptional activity. NR1H2 was found to regulate <i>AR</i> gene transcription; however, the NR1H2 variant showed normal activity. This study expands the <i>NR5A1</i>/SF-1 network of interacting partners, while not solving the exact interplay of different variants that might be involved in revealing the observed DSD phenotype. It also illustrates that understanding complex genetics in DSDs is challenging.