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Context Steroidogenic factor 1 (NR5A1 /SF-1) is a nuclear receptor that regulates sex development, steroidogenesis, and reproduction. Genetic variants in NR5A1 /SF-1 are common among differences of sex development (DSD) and associate with a wide range of phenotypes, but their pathogenic mechanisms remain unclear. Objective Novel, likely disease-causing NR5A1 /SF-1 variants from the SF1next cohort of individuals with DSD were characterized to elucidate their pathogenic effect. Methods Different in silico tools were used to predict the impact of novel NR5A1 /SF-1 variants on protein function. An extensive literature review was conducted to compare and select the best functional studies for testing the pathogenic effect of the variants in a classic cell culture model. The missense NR5A1 /SF-1 variants were tested on the promoter luciferase reporter vector -152CYP11A1 _pGL3 in HEK293T cells and assessed for their cytoplasmic/nuclear localization by Western blot. Results Thirty-five novel NR5A1 /SF-1 variants were identified in the SF1next cohort. Seventeen missense NR5A1 /SF-1 variants were functionally tested. Transactivation assays showed reduced activity for 40% of the variants located in the DNA binding domain and variable activity for variants located elsewhere. Translocation assessment revealed 3 variants (3/17) with affected nuclear translocation. No clear genotype-phenotype, structure-function correlation was found. Conclusion Genetic analyses and functional assays do not explain the observed wide phenotype of individuals with these novel NR5A1 /SF-1 variants. In 9 individuals, additional likely disease-causing variants in other genes were found, strengthening the hypothesis that the broad phenotype of DSD associated with NR5A1 /SF-1 variants may be caused by an oligogenic mechanism. [ABSTRACT FROM AUTHOR]

Background Steroidogenic Factor 1/Nuclear Receptor Subfamily 5 Group A Member 1 (SF-1/ NR5A1) is critical for the development and function of sex organs, influencing steroidogenesis and reproduction. While rare deleterious NR5A1 /SF-1 variants have been identified in individuals with various differences of sex development (DSD), primary ovarian insufficiency, and infertility, their impact on the general population remains unclear. Methods We analyzed health records and exome sequencing data from up to 420 162 individuals (227 858 women) from the UK Biobank study to assess the impact of rare (frequency < 0.1%) predicted deleterious NR5A1 /SF-1 variants on age at menopause and 26 other traits. Results No carriers of rare protein truncating variants in NR5A1 /SF-1 were identified. We found that the previously reported association of rare deleterious missense NR5A1 /SF-1 variants with earlier age at menopause is driven by variants in the DNA binding domain (DBD) and ligand binding domain (LBD) (combined test: beta = −2.36 years/allele, [95% CI: 3.21, −1.51], N = 107 carriers, P = 4.6 × 10−8). Carriers also had a higher risk of adult obesity (OR = 1.061, [95% CI: 1.003, 1.104], N = 344, P =.015), particularly among women (OR = 1.095 [95% CI: 1.034, 1.163, P = 3.87 × 10−3], N = 176), but not men (OR = 1.019, [95% CI: 0.955, 1.088], P =.57, N = 168). Conclusion Deleterious missense variants in the DBD and LBD likely disrupt NR5A1 /SF-1 function. This study broadens the relevance of deleterious NR5A1 /SF-1 variants beyond rare DSDs, suggesting the need for extended phenotyping and monitoring of affected individuals. [ABSTRACT FROM AUTHOR]

Steroidogenic factor 1 (SF-1) is a nuclear receptor that regulates steroidogenesis and reproductive development. NR5A1/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' NR5A1/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 NR1H2 and INHA associated with steroidogenesis, sex development, and reproduction. The identified variants were tested in cell models. Novel SF-1 and NR1H2 binding sites in the AR and INHA gene promoters were found. Transactivation studies showed that wild-type NR5A1/SF-1 regulates INHA and AR gene expression, while the NR5A1/SF-1 variant had decreased transcriptional activity. NR1H2 was found to regulate AR gene transcription; however, the NR1H2 variant showed normal activity. This study expands the NR5A1/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. [ABSTRACT FROM AUTHOR]

Background: Deviations of intrauterine sex determination and differentiation and postnatal sex development can result in a very heterogeneous group of differences of sex development (DSD) with a broad spectrum of phenotypes. Variants in genes involved in sexual development cause different types of DSD, but predicting the phenotype from an individual's genotype and vice versa remains challenging. Summary: Next Generation Sequencing (NGS) studies suggested that oligogenic inheritance contributes to the broad manifestation of DSD phenotypes. This review will focus on possible oligogenic inheritance in DSD identified by NGS studies with a special emphasis on NR5A1variants as an example of oligogenic origin associated with a broad range of DSD phenotypes. We thoroughly searched the literature for evidence regarding oligogenic inheritance in DSD diagnosis with NGS technology and describe the challenges to interpret contribution of these genes to DSD phenotypic variability and pathogenicity. Key Messages: Variants in common DSD genes like androgen receptor (AR), mitogen-activated protein kinase kinase kinase 1 (MAP3K1), Hydroxy-Delta-5-Steroid Dehydrogenase 3 Beta- And Steroid Delta-Isomerase 2 (HSD3B2), GATA Binding Protein 4 (GATA4), zinc finger protein friend of GATA family member 2 (ZFPM2), 17b-hydroxysteroid dehydrogenase type 3 (HSD17B3), mastermind-like domain-containing protein 1 (MAMLD1), and nuclear receptor subfamily 5 group A member 1 (NR5A1) have been detected in combination with additional variants in related genes in DSD patients with a broad range of phenotypes, implying a role of oligogenic inheritance in DSD, while still awaiting proof. Use of NGS approach for genetic diagnosis of DSD patients can reveal more complex genetic traits supporting the concept of oligogenic cause of DSD. However, assessing the pathomechanistic contribution of multiple gene variants on a DSD phenotype remains an unsolved conundrum. [ABSTRACT FROM AUTHOR]

Context: Steroidogenic factor 1 (NR5A1/SF-1) is a nuclear receptor that regulates sex development, steroidogenesis, and reproduction. Genetic variants in NR5A1/SF-1 are common among differences of sex development (DSD) and associate with a wide range of phenotypes, but their pathogenic mechanisms remain unclear., Objective: Novel, likely disease-causing NR5A1/SF-1 variants from the SF1next cohort of individuals with DSD were characterized to elucidate their pathogenic effect., Methods: Different in silico tools were used to predict the impact of novel NR5A1/SF-1 variants on protein function. An extensive literature review was conducted to compare and select the best functional studies for testing the pathogenic effect of the variants in a classic cell culture model. The missense NR5A1/SF-1 variants were tested on the promoter luciferase reporter vector -152CYP11A1&#95;pGL3 in HEK293T cells and assessed for their cytoplasmic/nuclear localization by Western blot., Results: Thirty-five novel NR5A1/SF-1 variants were identified in the SF1next cohort. Seventeen missense NR5A1/SF-1 variants were functionally tested. Transactivation assays showed reduced activity for 40% of the variants located in the DNA binding domain and variable activity for variants located elsewhere. Translocation assessment revealed 3 variants (3/17) with affected nuclear translocation. No clear genotype-phenotype, structure-function correlation was found., Conclusion: Genetic analyses and functional assays do not explain the observed wide phenotype of individuals with these novel NR5A1/SF-1 variants. In 9 individuals, additional likely disease-causing variants in other genes were found, strengthening the hypothesis that the broad phenotype of DSD associated with NR5A1/SF-1 variants may be caused by an oligogenic mechanism., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

Background: Steroidogenic Factor 1/Nuclear Receptor Subfamily 5 Group A Member 1 (SF-1/ NR5A1 ) is critical for the development and function of sex organs, influencing steroidogenesis and reproduction. While rare deleterious NR5A1 /SF-1 variants have been identified in individuals with various differences of sex development (DSD), primary ovarian insufficiency, and infertility, their impact on the general population remains unclear., Methods: We analyzed health records and exome sequencing data from up to 420 162 individuals (227 858 women) from the UK Biobank study to assess the impact of rare (frequency < 0.1%) predicted deleterious NR5A1 /SF-1 variants on age at menopause and 26 other traits., Results: No carriers of rare protein truncating variants in NR5A1 /SF-1 were identified. We found that the previously reported association of rare deleterious missense NR5A1 /SF-1 variants with earlier age at menopause is driven by variants in the DNA binding domain (DBD) and ligand binding domain (LBD) (combined test: beta = -2.36 years/allele, [95% CI: 3.21, -1.51], N = 107 carriers, P = 4.6 × 10 -8 ). Carriers also had a higher risk of adult obesity (OR = 1.061, [95% CI: 1.003, 1.104], N = 344, P = .015), particularly among women (OR = 1.095 [95% CI: 1.034, 1.163, P = 3.87 × 10 -3 ], N = 176), but not men (OR = 1.019, [95% CI: 0.955, 1.088], P = .57, N = 168)., Conclusion: Deleterious missense variants in the DBD and LBD likely disrupt NR5A1 /SF-1 function. This study broadens the relevance of deleterious NR5A1 /SF-1 variants beyond rare DSDs, suggesting the need for extended phenotyping and monitoring of affected individuals., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)