ArticleThe Journal of clinical endocrinology and metabolism2025
Characterization of 35 Novel NR5A1/SF-1 Variants Identified in Individuals With Atypical Sexual Development: The SF1next Study.
Article in The Journal of clinical endocrinology and metabolism, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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Who cites it
8 citing papers in PubMed, 10 citations in OpenAlex.
- Close relationship, similar phenotype of GATA4 and NR5A1 mutations: gonadal dysgenesis and puberty development.Journal of endocrinological investigation · 2025Article
- NR5A1 gene variants in infertile Senegalese men: Discovery of a novel missense variant and genotype-phenotype correlation.Journal, genetic engineering & biotechnology · 2025Article
- Two Cases of 46,XY Differences of Sex Development Due to Gonadal Dysgenesis Associated With NovelJCEM case reports · 2025Article
- Oligogenic analysis across broad phenotypes of 46,XY differences in sex development associated with NR5A1/SF-1 variants: findings from the international SF1next study.EBioMedicine · 2025Article
- Characterization of 35 Novel NR5A1/SF-1 Variants Identified in Individuals With Atypical Sexual Development: The SF1next Study.The Journal of clinical endocrinology and metabolism · 2025Article
- Gene therapy for disorders of sex development: current applications and future challenges.Frontiers in genetics · 2025Review
- Article
- Role ofCurrent issues in molecular biology · 2024Review
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Authors and funding
7 authors at 2 institutions in 3 countries.
Funding
Abstract
contextSteroidogenic 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.
objectiveNovel, likely disease-causing NR5A1/SF-1 variants from the SF1next cohort of individuals with DSD were characterized to elucidate their pathogenic effect.
methodsDifferent 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.
resultsThirty-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.
conclusionGenetic 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.
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