TY - JOUR
T1 - Characterization of 35 Novel NR5A1/SF-1 Variants Identified in Individuals With Atypical Sexual Development
T2 - The SF1next Study
AU - SF1next study group
AU - Naamneh Elzenaty, Rawda
AU - Martinez de Lapiscina, Idoia
AU - Kouri, Chrysanthi
AU - Sauter, Kay Sara
AU - Sommer, Grit
AU - Castaño, Luis
AU - Flück, Christa E.
AU - Abali, S.
AU - Abali, Z. Y.
AU - Ahmed, F.
AU - Akin, L.
AU - Almaraz, M. C.
AU - Audí, L.
AU - Aydin, M.
AU - Balsamo, A.
AU - Baronio, F.
AU - Bryce, J.
AU - Busiah, K.
AU - Caimari, M.
AU - CamatsTarruella, N.
AU - Campos-Martorell, A.
AU - Casteràs, A.
AU - Çetinkaya, S.
AU - Chan, Y. M.
AU - Claahsen-Van der Grinten, H. L.
AU - Costa, I.
AU - Cools, M.
AU - Darendeliler, F. F.
AU - Davies, J. H.
AU - Esteva, I.
AU - Fabbri-Scallet, H.
AU - Finlayson, C. A.
AU - Garcia, E.
AU - Garcia-Cuartero, B.
AU - German, A.
AU - Globa, E.
AU - Guerra, G.
AU - Guerrero, J.
AU - Guran, T.
AU - Hannema, S. E.
AU - Hiort, O.
AU - Hirsch, J.
AU - Hughes, I.
AU - Janner, M.
AU - Kolesinska, Z.
AU - Lachlan, K.
AU - L'Allemand, D.
AU - Malikova, J. K.
AU - Lang-Muritano, M.
AU - Zangen, D.
N1 - Publisher Copyright:
© 2024 The Author(s). Published by Oxford University Press on behalf of the Endocrine Society.
PY - 2025/3/1
Y1 - 2025/3/1
N2 - 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.
AB - 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.
KW - broad phenotype
KW - differences of sex development (DSD)
KW - genotype-phenotype correlation
KW - steroidogenic factor 1 (SF-1/NR5A1)
UR - http://www.scopus.com/inward/record.url?scp=85194255083&partnerID=8YFLogxK
U2 - 10.1210/clinem/dgae251
DO - 10.1210/clinem/dgae251
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C2 - 38623954
AN - SCOPUS:85194255083
SN - 0021-972X
VL - 110
SP - e675-e693
JO - Journal of Clinical Endocrinology and Metabolism
JF - Journal of Clinical Endocrinology and Metabolism
IS - 3
ER -