A Mutated Form of Steroidogenic Factor 1 (SF-1 G35E) That Causes Sex Reversal in Humans Fails to Synergize with Transcription Factor GATA-4

Abstract

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 Mü llerian-inhibiting substance hormone that induces regression of the Mü llerian 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.

Testicular differentiation factor SF-1 is required for human spleen development

“…In contrast to the recessive SF1 mutations, impairment of TESCO activation by G35E (which is known to cause autosomal-dominant DSD; ref. 20) remained even with coexpression of SRY or SOX-9, and similar results were obtained in CHO cells ( Figure 3B and Supplemental Figure 3). This qualitative difference between recessive mutations and a severe dominant SF1 mutation was not (7), showing the DNA-binding domain bound to its target sequence in the inhibin α subunit promoter.…”

Loss-of-function mutation in GATA4 causes anomalies of human testicular development

“…GATA4 binds to NR5A1 to synergistically enhance the expression of AMH by regulating its promoter (24). We studied the ability of p.Gly221Arg mutant to retain this synergy.…”

“…GATA4 functionally interacts with NR5A1 in primary Sertoli cell cultures to positively regulate the expression of AMH, through two complementary mechanisms, either by binding to its site on the AMH promoter or by direct interaction with NR5A1 when either NR5A1 alone or both GATA4 and NR5A1 are bound to their respective sites on the AMH promoter (18). Mutations in NR5A1 may cause 46,XY DSD through a lack of appropriate interaction with GATA4 (24). No mutations in GATA4 have been reported in association with human cases of DSD.…”

Adrenocortical tumorigenesis, luteinizing hormone receptor and transcription factors GATA-4 and GATA-6

“…There is also co-operation between GATA-4 and SF-1 to regulate the expression of AMH (anti-Müllerian hormone) ). The lack of co-operation of these two substances could be the reason for some cases of abnormal sex differentiation in humans (Tremblay and Viger 2003). Recently it has also been found that the human HSD3B2 promoter is activated by GATA transcription factors (Martin et al 2005), presumably by GATA-6 (Bassett et al 2005).…”