• PMID: 12907682
• Gene Name: NR5A1
• Condition: Sex reversal
• Association: Thus, our results strengthen the importance of a GATA-4/SF-1 cooperation for MIS transcription and reveal that disruption of this synergism might be responsible for some cases of abnormal sex differentiation in humans.
• Mutation: G35E
• Sex: Male infertility, Female infertility
• Infertility type: Male infertility, Female infertility
• Other associated phenotypes: Sex reversal

A mutated form of steroidogenic factor 1 (SF-1 G35E) that causes sex reversal in humans fails to synergize with transcription factor GATA-4

Tremblay JJ, Viger RS.

Steroidogenic factor 1 (SF-1) is a transcription factor belonging to the nuclear receptor superfamily. SF-1 regulates the expression of many genes involved in reproduction, steroidogenesis, and sexual differentiation. An important SF-1 target for male sexual differentiation is the gene encoding the Müllerian-inhibiting substance hormone that induces regression of the Müllerian ducts in the developing male embryo. Not long ago, a mutation (G35E) in the human SF-1 gene was identified as the cause of sex reversal and adrenal failure in a phenotypically female but genotypically XY individual. This suggested that the mutated SF-1 protein might interfere with the expression of SF-1 target gene(s) involved in the male sexual differentiation pathway, such as MIS. Surprisingly, the initial biochemical characterization of the SF-1 G35E mutant revealed that it could bind and activate the MIS promoter as efficiently as wild-type SF-1. MIS expression, however, does not rely solely on SF-1 but rather requires the concerted action of several transcription factors including GATA-4. We have previously reported that GATA-4 and SF-1 transcriptionally cooperate to synergistically activate the MIS promoter. Thus, we hypothesized that the phenotype observed with the SF-1 G35E mutation could be explained, at least in part, by a failure and/or a disruption of GATA-4/SF-1 synergism. We found that the SF-1 G35E mutant failed to synergize with GATA-4 despite a direct physical interaction between the two proteins. Interestingly, the SF-1 G35E mutant also disrupted transcriptional synergism between wild-type SF-1 and GATA-4, indicating that it could act as a dominant negative competitor. Thus, our results strengthen the importance of a GATA-4/SF-1 cooperation for MIS transcription and reveal that disruption of this synergism might be responsible for some cases of abnormal sex differentiation in humans. FAU - Tremblay, Jacques J AU - Tremblay JJ AD - Ontogeny-Reproduction Research Unit, CHUL Research Centre and Centre de Recherche en Biologie de la Reproduction, Department of Obstetrics and Gynecology, Université Laval, 2705 Laurier Boulevard, Sainte-Foy, Quebec G1V 4G2, Canada.