Naamneh Elzenaty, Rawda; Martinez de Lapiscina, Idoia; Kouri, Chrysanthi; Sauter, Kay-Sara; Sommer, Grit; Castaño, Luis; Flück, Christa E (2024). Characterization of 35 novel NR5A1/SF-1 variants identified in individuals with atypical sexual development: The SF1next study. (In Press). The journal of clinical endocrinology and metabolism Oxford University Press 10.1210/clinem/dgae251
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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 three variants (3/17) with affected nuclear translocation. No clear genotype-phenotype, structure-function correlation was found.
CONCLUSIONS
Genetic analyses and functional assays do not explain the observed wide phenotype of individuals with these novel NR5A1/SF-1 variants. In nine 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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