Characterization of 35 Novel NR5A1/SF-1 Variants Identified in Individuals With Atypical Sexual Development: The SF1next Study

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00064203%3A_____%2F25%3A10494888" target="_blank" >RIV/00064203:_____/25:10494888 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/00216208:11130/25:10494888

Výsledek na webu

<a href="https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=dQlDilQCtx" target="_blank" >https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=dQlDilQCtx</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1210/clinem/dgae251" target="_blank" >10.1210/clinem/dgae251</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Characterization of 35 Novel NR5A1/SF-1 Variants Identified in Individuals With Atypical Sexual Development: The SF1next Study

Popis výsledku v původním jazyce

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.

Název v anglickém jazyce

Characterization of 35 Novel NR5A1/SF-1 Variants Identified in Individuals With Atypical Sexual Development: The SF1next Study

Popis výsledku anglicky

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.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30209 - Paediatrics

Projekt

—

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2025

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

The Journal of Clinical Endocrinology &amp; Metabolism

ISSN

0021-972X

e-ISSN

1945-7197

Svazek periodika

110

Číslo periodika v rámci svazku

3

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

19

Strana od-do

"e675"-"e693"

Kód UT WoS článku

001214471000001

EID výsledku v databázi Scopus

2-s2.0-85194255083