LRH-1 May Rescue SF-1 Deficiency for Steroidogenesis: An in vitro and in vivo Study

Area of Science:

• Endocrinology
• Genetics
• Molecular Biology

Background:

• Mutations in Steroidogenic Factor 1 (NR5A1/SF-1) lead to diverse disorders of sex development in 46,XY individuals and ovarian insufficiency in 46,XX women.
• The lack of a clear genotype-phenotype correlation suggests potential involvement of other genes, with Liver Receptor Homologue-1 (LRH-1/NR5A2) being a candidate due to functional similarities.

Purpose of the Study:

• To investigate the potential compensatory role of LRH-1 in SF-1 deficiency.
• To explore the interplay between SF-1, LRH-1, and DAX-1.
• To analyze NR5A2 gene mutations in patients with NR5A1 mutations.

Main Methods:

• In vitro studies assessing the transactivation activity of LRH-1 isoforms on target gene promoters (CYP17A1, HSD3B2).
• Analysis of SF-1, LRH-1, and DAX-1 interactions.
• Expression profiling of LRH-1 in human steroidogenic tissues.
• Genetic screening of the NR5A2 gene in a cohort of patients with NR5A1 mutations.

Main Results:

• LRH-1 isoforms demonstrated similar transactivation capabilities to SF-1 and could compensate for SF-1 deficiency in vitro.
• DAX-1 was found to inhibit the transactivation mediated by both SF-1 and LRH-1.
• LRH-1 expression was detected in human fetal and adult adrenal glands and testes.
• No NR5A2/LRH-1 mutations were identified in the studied cohort of patients with NR5A1 mutations.

Conclusions:

• LRH-1 can functionally substitute for SF-1 in vitro, suggesting a potential role in steroidogenesis.
• The expression of LRH-1 in fetal testes indicates a possible role in male gonadal development.
• The absence of NR5A2 mutations indicates that LRH-1 is not the 'second genetic hit' responsible for the wide phenotypic variability observed in patients with NR5A1 mutations.