Steroidogenic factor-1 (SF-1, NR5A1) and human disease

A p.G146A polymorphism (rs1110061; c.624G>C) in SF-1 has been reported to be associated with micropenis or cryptorchidism in two relatively small studies of patients from Japan ( Wada et al., 2005, 2006 ). This variant has potentially reduced function in some assay systems. Limited data have suggested that the presence of this p.G146A change together with haploinsufficiency of NR5A1 may be associated with a more severe 46,XY DSD (see Section 4.2 ) ( Köhler et al., 2008 ). However, more studies are needed before the true significance of this potential effect is known.

The authors were supported by a Wellcome Trust Senior Research Fellowship in Clinical Science (079666, to JCA) and a PhD studentship from Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (Capes, Brazil) (4798066, to BFdS). The funders played no role in the preparation of the manuscript or the decision to submit the paper for publication.

NR5A1 mutations have also now been identified in familial and sporadic forms of 46,XX primary ovarian insufficiency (POI) ( Fig. 2 ) ( Lourenco et al., 2009 ). These 46,XX patients with NR5A1 mutations presented with either primary or secondary amenorrhea, and with a variable age of onset of features. Primary gonadal failure was shown by elevated LH and FSH levels and low estradiol. In the one case studied, an ovarian biopsy showed extensive fibrosis with no evidence of follicles ( Fig. 3 D). Most of these women harbored heterozygous alterations in NR5A1 and had been identified on account of a history of 46,XY DSD and 46,XX POI in different individuals within the same family. In one large kindred a partial loss-of-function SF-1 change (p.D293N) was inherited in an autosomal recessive manner. Heterozygous SF-1/ NR5A1 changes were also found in two girls with sporadic forms of POI and no family history. Therefore, although some 46,XX women with NR5A1 mutations have been described to have normal ovarian function and can transmit the mutation in a sex-limited dominant fashion, the detection of NR5A1 alterations in 46,XX ovarian failure shows that SF-1 is also a key factor in ovarian development and function in humans. Disruption of SF-1 may affect the ovary at multiple levels, including reduced germ cell number, impaired stromal integrity, abnormal folliculogenesis and defective steroidogenesis. Some of these women may go through a stage of decreased ovarian reserve (with decreasing AMH and elevating gonadotropins) before manifesting clinical signs or symptoms of ovarian failure ( Warman et al., 2010 ). Although more studies are needed to understand the natural history of these changes in more detail, and to establish how prevalent or predictable ovarian dysfunction might be, these cases do highlight that SF-1 plays a role in human ovarian function too.

Steroidogenic factor-1 (SF-1, NR5A1 , Ad4BP) was originally identified as a master-regulator of steroidogenic enzymes in the early 1990s following the seminal work of Keith L. Parker and Ken-ichirou Morohashi ( Rice et al., 1991; Lala et al., 1992; Morohashi et al., 1992 ). SF-1 has since been shown to control many aspects of adrenal and reproductive function, and many factors involved in the development of these structures have been shown to be regulated by SF-1 ( Parker and Schimmer, 1997; Lin and Achermann, 2008; Schimmer and White, 2010 ). In addition to numerous in vitro studies, significant early progress in understanding the in vivo function of SF-1 was obtained following deletion of the gene encoding Sf-1 ( Nr5a1 ) in the mouse ( Luo et al., 1994; Sadovsky et al., 1995; Shinoda et al., 1995 ). Homozygous null mice (−/−) have adrenal agenesis, complete testicular dysgenesis, persistent Müllerian structures in XY animals, partial hypogonadotropic hypogonadism, and other features such as hyposplenism, abnormalities of the ventro-medial hypothalamus and late-onset obesity ( Majdic et al., 2002 ). Haploinsufficient animals were originally thought to have minimal phenotypes compared to the severe features seen in Nr5a1 null littermates. However, more subtle phenotypes have also been found to be present in haploinsufficient animals following more detailed investigation ( Bland et al., 2000, 2004 ), and newer molecular and transgenic strategies continue to elucidate the role SF-1 plays as a critical mediator of endocrine development and function ( Ferraz-de-Souza et al., 2009; Hoivik et al., 2010 ). In parallel with these in vitro and in vivo studies, it has emerged that SF-1 is also an important factor in several human diseases. It is more than a decade since the first case of human SF-1 disruption was described. At that time it seemed likely that SF-1 changes in humans would be rare events associated with specific phenotypes. However, more recent studies are revealing that variations in SF-1 may play a much greater role in human disease than was originally thought. Here, we review the range of human phenotypes that are emerging in association with SF-1/ NR5A1 variants. It is also worth noting that – to date – no complete deletions of NR5A1 have been described; thus, it is not completely established whether complete loss of SF-1 is compatible with embryonic or fetal survival in humans.

The authors have no conflict of interest to declare.

SF-1 is clearly an important mediator of adrenal and reproductive function in humans. Changes in SF-1 activity have now been reported in association with a range of human conditions. Some of these conditions are rare, sporadic events due to “private” de novo changes in the coding sequence of NR5A1 in an individual's genome. However, it is also emerging that specific changes in SF-1 may contribute to more common conditions such as male factor infertility or primary ovarian insufficiency. The exact pathogenic mechanisms in some of these cases are not entirely clear and phenotypes can be variable in some cases. Therefore, changes in SF-1 are likely to predispose an individual to a given phenotype but the ultimate clinical picture may be influenced by a number of oligogenic modulators, developmental switches, epigenetic influences, environmental stimuli and even imbalanced cis-regulation of mutant versus wild-type alleles when mutations are present in a heterozygous state. More systematic studies of SF-1 in different patient cohorts will be needed to address the natural history of some of these conditions and whether detecting a change in SF-1 might predispose to late-onset adrenal insufficiency, differences in tumor risk, or be important when exploring options for fertility preservation. Furthermore, the effects of SF-1 in tumorigenesis and in other physiological systems (e.g. appetite regulation, obesity, anxiety) might be important if data from mouse studies are extrapolated into humans ( Schimmer and White, 2010 ). The next decade of human SF-1 research promises to be as exciting as the last.

Whilst most studies have focused on loss of function of SF-1 and human disease, it is also becoming apparent that overexpression or overactivity of SF-1 might have an important clinical effect. SF-1 overexpression could result from (1) genomic duplications of the chromosomal locus containing NR5A1 resulting in biologically significant copy number variation (CNV), or from (2) upregulation of NR5A1 gene transcription due to increased promoter/enhancer activity or following decreased promoter methylation. Alternatively, overactivity of SF-1 could result from (1) increased protein stabilization or reduced degradation, (2) loss of SUMOylation-dependent repression of transcriptional activity, or (3) specific changes in the structure of SF-1 that result in increased basal activity or increased affinity for native and/or alternative ligands. Several of these mechanisms are now being seen as potential causes or modifiers of human disease, which has translational implications as pharmacomodulation of SF-1 might have a potential role in the treatment of these conditions ( Schimmer and White, 2010 ). Somatic duplications of 9q33 including NR5A1 were originally described in 2005 in a cohort of children from Brazil with adrenocortical tumors (ACTs) ( Figueiredo et al., 2005 ). These changes occurred largely on the background of loss of heterozygosity for the tumor suppressor gene p53 (TP53). Increased NR5A1 expression was subsequently confirmed in an independent study of ACTs, with a higher number of pediatric tumors showing NR5A1 overexpression compared to adult tumors ( Almeida et al., 2010 ). Interestingly, increased nuclear SF-1 protein expression was seen in many cases, sometimes independently of detectable NR5A1 gene expression. This finding as been supported by recent data from analysis of a large cohort of adult ACTs, which has shown a correlation between higher SF-1 protein levels and worse prognosis ( Sbiera et al., 2010 ). Of note, SF-1 overexpression has been shown to increase proliferation and to decrease apoptosis of human adrenocortical cells, and to induce ACTs in transgenic mice ( Doghman et al., 2007 ). SF-1 inverse agonists have been shown to inhibit adrenocortical carcinoma cell proliferation in vitro ( Doghman et al., 2009 ). A heterozygous point mutation (p.R365P) has been reported in a woman with polycystic ovary syndrome ( Calvo et al., 2001 ). The functional or clinical significance of this finding is unclear, but raises the possibility that conformational changes in the ligand-binding domain of SF-1 could have a biological effect. SF-1 has been shown to be expressed in endometriotic cells whereas it is not usually detected in normal endometrium ( Xue et al., 2007 ). Part of this aberrant expression may be the result of hypomethylation of a CpG-rich region in its proximal promoter region with subsequent activation by upstream stimulatory factor 2 (USF2) ( Xue et al., 2007; Utsunomiya et al., 2008 ). Alternatively, SF-1 activity in endometriotic tissue may be increased following stimulation of the GPR30 estrogen receptor ( Lin et al., 2009 ). Increased SF-1 expression or activity in endometriotic tissue could result in increased activity of StAR and aromatase, resulting in increased local estrogen synthesis, a key pathological feature of this condition ( Utsunomiya et al., 2008 ).