title: LRH-1 May Rescue SF-1 Deficiency for Steroidogenesis: An in vitro and in vivo Study.
abstract: 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.
authors.affiliation: Department of Pediatrics and Clinical Research, University Children's Hospital, Bern, Switzerland.
authors.forename: Núria
authors.initials: N
authors.lastname: Camats
authors.forename: Laura
authors.initials: L
authors.lastname: Audí
authors.forename: Mónica
authors.initials: M
authors.lastname: Fernández-Cancio
authors.forename: Pilar
authors.initials: P
authors.lastname: Andaluz
authors.forename: Primus E
authors.initials: PE
authors.lastname: Mullis
authors.forename: Antonio
authors.initials: A
authors.lastname: Carrascosa
authors.forename: Christa E
authors.initials: CE
authors.lastname: Flück
mesh_terms: D057137:DAX-1 Orphan Nuclear Receptor / Q000235:genetics; D057809:HEK293 Cells; D006579:Heterozygote; D006801:Humans; D009154:Mutation / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics* / Q000378:metabolism; D054339:Steroidogenic Factor 1 / Q000235:genetics* / Q000378:metabolism; D013256:Steroids / Q000096:biosynthesis*; D015533:Transcriptional Activation / Q000235:genetics
chemical_list: D057137:DAX-1 Orphan Nuclear Receptor; C539965:NR0B1 protein, human; C515057:NR5A1 protein, human; C082631:NR5A2 protein, human; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D054339:Steroidogenic Factor 1; D013256:Steroids