Camats Tarruella, Núria; Audí, Laura; Fernández-Cancio, Mónica; Andaluz, Pilar; Mullis, Primus-Eugen; Carrascosa, Antonio; Flück, Christa Emma (2015). LRH-1 May Rescue SF-1 Deficiency for Steroidogenesis: An in vitro and in vivo Study. Sexual development, 9(3), pp. 144-154. Karger 10.1159/000381575
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Steroidogenic factor 1 (NR5A1/SF-1) mutations usually manifest in 46,XY individuals with variable degrees of disordered sex development and in 46,XX women with ovarian insufficiency. So far, there is no genotype-phenotype correlation. The broad spectrum of phenotype with NR5A1 mutations may be due to a second hit in a gene with similar function to NR5A1/SF-1. Liver receptor homologue-1 (LRH-1/NR5A2) might be a good candidate. We performed in vitro studies for the interplay between SF-1, LRH-1 and DAX-1, expression profiles in human steroidogenic tissues, and NR5A2 genetic studies in a cohort (11 patients, 8 relatives, 11 families) harboring heterozygote NR5A1/SF-1 mutations. LRH-1 isoforms transactivate the CYP17A1 and HSD3B2 promoters similarly to SF-1 and compensate for SF-1 deficiency. DAX-1 inhibits SF-1- and LRH-1-mediated transactivation. LRH-1 is found expressed in human adult and fetal adrenals and testes. However, no NR5A2/LRH-1 mutations were detected in 14 individuals with heterozygote NR5A1/SF-1 mutations. These findings demonstrate that in vitro LRH-1 can act like SF-1 and compensate for its deficiency. Expression of LRH-1 in fetal testis suggests a role in male gonadal development. However, as we found no NR5A2/LRH-1 mutations, the 'second genetic hit' in SF-1 patients explaining the broad phenotypic variability remains elusive.
Item Type: |
Journal Article (Original Article) |
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Division/Institute: |
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > Unit Childrens Hospital > Forschungsgruppe Endokrinologie / Diabetologie / Metabolik (Pädiatrie) 04 Faculty of Medicine > Department of Gynaecology, Paediatrics and Endocrinology (DFKE) > Clinic of Paediatric Medicine |
UniBE Contributor: |
Camats Tarruella, Núria, Mullis, Primus-Eugen, Flück Pandey, Christa Emma |
Subjects: |
600 Technology > 610 Medicine & health |
ISSN: |
1661-5425 |
Publisher: |
Karger |
Language: |
English |
Submitter: |
Anette van Dorland |
Date Deposited: |
07 Apr 2016 15:47 |
Last Modified: |
02 Mar 2023 23:27 |
Publisher DOI: |
10.1159/000381575 |
PubMed ID: |
25896302 |
BORIS DOI: |
10.7892/boris.79275 |
URI: |
https://boris.unibe.ch/id/eprint/79275 |
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