Steroidogenic factor 1 (SF-1) protein and a few related things

February 5, 2024
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The steroidogenic factor 1 (SF-1) protein is a transcription factor involved in sex determination by controlling the activity of genes related to the reproductive glands or gonads and adrenal glands. This protein is encoded by the NR5A1 gene, a member of the nuclear receptor subfamily, located on the long arm of chromosome 9 at position 33.3. It was originally identified as a regulator of genes encoding cytochrome P450 steroid hydroxylases, however, further roles in endocrine function have since been discovered.

Structure

The NR5A1 gene encodes a 461-amino acid protein that shares several conserved domains consistent with members of the nuclear receptor subfamily. The N-terminal domain includes two zinc fingers and is responsible for DNA binding via specific recognition of target sequences. Variations of AGGTCA DNA motifs allows SF-1 to interact with the major groove of the DNA helix and monomerically bind. Following binding, trans-activation of target genes depends on recruitment of co-activators such as SRC-1, GRIP1, PNRC, or GCN5. Other critical domains of SF-1 include a proline-rich hinge region, ligand-binding domain, and a C-terminal activation domain for transcriptional interactions. A 30-amino acid extension of the DNA-binding domain known as the A-box stabilizes monomeric binding by acting as a DNA anchor. The hinge region can undergo post-transcriptional and translational modifications such as phosphorylation by cAMP-dependent kinase, that further enhance stability and transcriptional activity.

SF-1 is considered an orphan receptor as high-affinity naturally occurring ligands have yet to be identified.

Homology

Analysis of mouse SF-1 cDNA revealed sequence similarities with Drosophila fushi tarazu factor I (FTZ-F1) which regulates the fushi tarazu homeobox gene. Several other FTZ-F1 homologs have been identified that implicate high level of sequence conservation among vertebrates and invertebrates. For example, SF-1 cDNA shares an identical 1017 base-pair sequence with embryonal long terminal repeat-binding protein (ELP) cDNA isolated from embryonal carcinoma cells, differing only in their terminal ends.

Expression

Adult steroidogenic tissue

SF-1 expression is localized to adult steroidogenic tissues correlating with known expression profiles of steroid hydroxylases. Using in situ hybridization with SF-1 cRNA specific probe detected gene transcripts in adrenocortical cells, Leydig cells, and ovarian theca and granulosa cells. SF-1 specific antibody studies confirmed expression profile of SF-1 in rats and humans corresponding to sites of transcript detection.

Embryonic steroidogenic tissue

Genetic sex in mammals is determined by the presence or absence of the Y chromosome at fertilization. Sexually dimorphic development of embryonic gonads into testes or ovaries is activated by the SRY gene product. Sexual differentiation is then directed by hormones produced by embryonic testes, the presence of ovaries, or complete absence of gonads. SF-1 transcripts initially localize to the urogenital ridge before SF-1 expressing cells resolve into distinct adrenocortical and gonadal precursors that ultimately give rise to adrenal cortex and gonads.

SF-1 transcripts precede the onset of SRY expression in the fetal testes hinting at gonadal developmental role. SRY influences the differentiation of the fetal testes into distinct compartments: testicular cords and interstitial region containing Leydig cells. Increase in SF-1 protein and detection in the steroidogenic Leydig cells and testicular cords coincides with development.

However, in the ovaries, gonadal sexual differentiation is facilitated by reductions in SF-1 transcript and protein. SF-1 levels is strongly expressed at the onset of follicular development in theca and granulosa cells which precedes expression of the aromatase enzyme responsible for estrogen biosynthesis.

Other sites

Embryonic mouse SF-1 transcripts have been discovered to localize within regions of the developing diencephalon and subsequently in the ventromedial hypothalamic nucleus (VMH) suggesting roles beyond steroidogenic maintenance.

The ventromedial nucleus of the hypothalamus (VMN, VMH or ventromedial hypothalamus) is a nucleus of the hypothalamus. In 2007, Kurrasch et al. found that the ventromedial hypothalamus is a distinct morphological nucleus involved in terminating hunger, fear, thermoregulation, and sexual activity.

This nuclear region is involved in the recognition of the feeling of fullness.

It has four subdivisions:

  • Anterior (VMHa)
  • Dorsomedial (VMHdm)
  • Ventrolateral (VMHvl)
  • Central (VMHc)

These subdivisions differ anatomically, neurochemically, and behaviorally.

The ventromedial nucleus (VMN) is most commonly associated with satiety. Early studies showed that VMN lesions caused over-eating and obesity in rats. However, the interpretation of these experiments was summarily discredited when Gold’s research demonstrated that precision lesioning of the VMN did not result in hyperphagia. Nevertheless, numerous studies have shown that the immediacy of hyperphagia and obesity syndrome are a consequence of VMN lesions or procaine injections, and point to the VMN’s role in satiety. A major review of the subject in 2006 concluded that, “anatomical studies done both before and after Gold’s study did not replicate his results with lesions, and in nearly every published direct comparison of VMH lesions vs. PVN or VNAB lesions, the group with VMH lesions ate substantially more food and gained twice as much weight.” This strongly substantiates the classification of VMN as the primary satiety center in the hypothalamus.

It has also been found that lesions to the VMH in rats caused increased plasma insulin levels. Rats with a VMH lesion compared to normal rats overproduce a circulating satiety factor, to which the control rats can respond and rats with a VMH lesion cannot respond. A lesion to the VMH makes rats overproduce leptin, which they cannot respond to causing them to over eat, leading to obesity.

Researchers looked at a series of twenty-one animals of various degrees of adiposity, with respect to growth appearance, fat distribution, general physical condition, and the correlation between the level of adiposity attained and the correlation of the hypothalamic lesion. Lesions in the hypothalamic area, particularly the region of the ventromedial hypothalamus interrupts a large number of the descending fibers from the hypothalamic cell groups that were found to contribute to obesity in rats.

Another study found that there seems to be a higher concentration of cannabinoid receptor mRNA within the VMH in comparison to other nuclei within the hypothalamus. The cannabinoid ingestion has been linked to rewarding processes, and also with the release of dopamine in the brain.

VMH is also important in mammal play behaviour. Lesions to VMH along with the hippocampus, amygdala, the cerebellum, and the lateral hypothalamus are all linked to reduced play.

The VMHdm has a role in the male vocalizations and scent marking behaviors.

  • Flanagan-Cato LM, Lee BJ, Calizo LH (June 2006). “Co-localization of midbrain projections, progestin receptors, and mating-induced fos in the hypothalamic ventromedial nucleus of the female rat”. Hormones and Behavior. 50 (1): 52–60. doi:10.1016/j.yhbeh.2006.01.012. PMID 16546183. S2CID 36201218.
  • Harding SM, McGinnis MY (October 2005). “Microlesions of the ventromedial nucleus of the hypothalamus: effects on sociosexual behaviors in male rats”. Behavioral Neuroscience. 119 (5): 1227–34. doi:10.1037/0735-7044.119.5.1227. PMID 16300430.

The VMHvl contains many distinct neuronal populations that contribute to varying, often distinct, functions. Notably, this region plays a role in sexual behaviors in females (lordosis), thus stimulating their sexual arousal. The VMHvl has also been found to play a role in estrogen-mediated movement  and energy expenditure/thermogenesis.

Bilateral FOS expression in the VMH after repeated seizures is associated with alteration in the severity of flurothyl induced seizures in C57BL/6J mice that are not present in DBA/2J mice. Moreover, bilateral lesions of the VMH are able to block the propagation of seizure discharge to enter the brainstem seizure system.

Surgery

In West Germany, at least 70 men had their VMN operated on between 1962 and 1979. Most of these individuals had been involuntarily institutionalized or imprisoned for deviant sexual behavior, such as homosexuality, perceived hypersexuality among heterosexual men, and pedophilia. This surgery was not commonly performed elsewhere.

  • Rieber, Inge; Sigusch, Volkmar (1979). “Psychosurgery on sex offenders and sexual ?deviants? in West Germany”. Archives of Sexual Behavior. 8 (6): 523–527. doi:10.1007/BF01541419. PMID 391177. S2CID 41463669.

RT-PCR approaches have detected transcripts of mice FTZ-F1 gene in the placenta and spleen; and SF-1 transcripts in the human placenta.

Post-translational regulation

Transcription capacity of SF-1 can be influenced by post-translational modification. Specifically, phosphorylation of serine 203 is mediated by cyclin-dependent kinase 7. Mutations to CDK7 prevent interaction with the basal transcription factor, TFIIH, and formation of CDK-activating kinase complex. This inactivity has shown to repress phosphorylation of SF-1 and SF-1-dependent transcription.

Function

SF-1 is a critical regulator of reproduction, regulating the transcription of key genes involved in sexual development and reproduction, most notably StAR and P450SCC. It can form a transcriptional complex with TDF to up-regulate transcription of the Sox9 gene. Its targets include genes at every level of the hypothalamic-pituitary-gonadal axis, as well as many genes involved in gonadal and adrenal steroidogenesis.

Cholesterol side-chain cleavage enzyme is commonly referred to as P450scc, where “scc” is an acronym for side-chaincleavage. P450scc is a mitochondrialenzyme that catalyzes conversion of cholesterol to pregnenolone. This is the first reaction in the process of steroidogenesis in all mammalian tissues that specialize in the production of various steroid hormones. P450scc is a member of the cytochrome P450 superfamily of enzymes (family 11, subfamily A, polypeptide 1) and is encoded by the CYP11A1 gene.

The systematic name of this enzyme class is cholesterol, reduced-adrenal-ferredoxin:oxygen oxidoreductase (side-chain-cleaving). Other names include:

  • C27-side-chain cleavage enzyme
  • cholesterol 20-22-desmolase
  • cholesterol C20-22 desmolase
  • cholesterol desmolase
  • cholesterol side-chain cleavage enzyme
  • cholesterol side-chain-cleaving enzyme
  • cytochrome P-450scc
  • desmolase, steroid 20-22
  • enzymes, cholesterol side-chain-cleaving
  • steroid 20-22 desmolase
  • steroid 20-22-lyase.

Tissue and intracellular localization

The highest level of the cholesterol side-chain cleavage system is found in the adrenal cortex and the corpus luteum. The system is also expressed at high levels in steroidogenic theca cells in the ovary, and Leydig cells in the testis. During pregnancy, the placenta also expresses significant levels of this enzyme system. P450scc is also present at much lower levels in several other tissue types, including the brain. In the adrenal cortex, the concentration of adrenodoxin is similar to that of P450scc, but adrenodoxin reductase is expressed at lower levels

Immunofluorescence studies using specific antibodies against P450scc system enzymes have demonstrated that proteins are located exclusively within the mitochondria. P450scc is associated with the inner mitochondrial membrane, facing the interior (matrix). Adrenodoxin and adrenodoxin reductase are soluble peripheral membrane proteins located inside the mitochondrial matrix that appear to associate with each other primarily through electrostatic interactions.

Mechanism of action

P450scc catalyzes the conversion of cholesterol to pregnenolone in three monooxygenase reactions. These involve 2 hydroxylations of the cholesterol side-chain, which generate, first, 22R-hydroxycholesterol and then 20alpha,22R-dihydroxycholesterol. The final step cleaves the bond between carbons 20 and 22, resulting in the production of pregnenolone and isocaproic aldehyde.

Each monooxygenase step requires 2 electrons (reducing equivalents). The initial source of the electrons is NADPH. The electrons are transferred from NADPH to P450scc via two electron transfer proteins: adrenodoxin reductase and adrenodoxin. All three proteins together constitute the cholesterol side-chain cleavage complex.

The involvement of three proteins in cholesterol side-chain cleavage reaction raises the question of whether the three proteins function as a ternary complex as reductase:adrenodoxin:P450. Both spectroscopic studies of adrenodoxin binding to P450scc and kinetic studies in the presence of varying concentrations of adrenodoxin reductase demonstrated that the reductase competes with P450scc for binding to adrenodoxin. These results demonstrated that the formation of a functional ternary complex is not possible. From these studies, it was concluded that the binding sites of adrenodoxin to its reductase and to P450 are overlapping and, as a consequence, adrenodoxin functions as a mobile electron shuttle between reductase and P450. These conclusions have been confirmed by structural analysis of adrenodoxin and P450 complex.

The process of electron transfer from NADPH to P450scc is not tightly coupled; that is, during electron transfer from adrenodoxin reductase via adrenodoxin to P450scc, a certain portion of the electrons leak outside of the chain and react with O2, generating superoxide radicals. Steroidogenic cells include a diverse array of antioxidant systems to cope with the radicals generated by the steroidogenic enzymes.

Regulation

In each steroidogenic cell, the expression of the P450scc system proteins is regulated by the trophic hormonal system specific for the cell type. In adrenal cortex cells from zona fasciculata, the expression of the mRNAs encoding all three P450scc proteins is induced by corticotropin (ACTH). The trophic hormones increase CYP11A1 gene expression through transcription factors such as steroidogenic factor 1 (SF-1), by the α isoform of activating protein 2 (AP-2) in the human, and many others. The production of this enzyme is inhibited notably by the nuclear receptor DAX-1.

P450scc is always active, however its activity is limited by the supply of cholesterol in the inner membrane. The supplying of cholesterol to this membrane (from the outer mitochondrial membrane) is, thus, considered the true rate-limiting step in steroid production. This step is mediated primarily by the steroidogenic acute regulatory protein (StAR or STARD1). Upon stimulation of a cell to make steroid, the amount of StAR available to transfer cholesterol to the inner membrane limits how fast the reaction can go (the acute phase). With prolonged (chronic) stimulation, it is thought that cholesterol supply becomes no longer an issue and that the capacity of the system to make steroid (i.e., level of P450scc in the mitochondria) is now more important.

Corticotropin (ACTH) is a hormone that is released from the anterior pituitary in response to stress situations. A study of the steroidogenic capacity of the adrenal cortex in infants with acute respiratory disease demonstrated that indeed during disease state there is a specific increase in the steroidogenic capacity for the synthesis of the glucocorticoid cortisol but not for the mineralocorticoid aldosterone or androgen DHEAS that are secreted from other zones of the adrenal cortex.

  • Hanukoglu A, Fried D, Nakash I, Hanukoglu I (November 1995). “Selective increases in adrenal steroidogenic capacity during acute respiratory disease in infants”. European Journal of Endocrinology. 133 (5): 552–556. doi:10.1530/eje.0.1330552. PMID 7581984. S2CID 44439040.

Mutations in the CYP11A1 gene result in a steroid hormone deficiency, causing a minority of cases of the rare and potentially fatal condition lipoid congenital adrenal hyperplasia. Deficiency of CYP11A1 can result in hyperpigmentation, hypoglycemia, and recurrent infections.

Cholesterol side-chain cleavage enzyme inhibitors include aminoglutethimide, ketoconazole, and mitotane, among others.

Enzymes, their cellular location, substrates and products in human steroidogenesis. Shown also is the major classes of steroid hormones: progestogens, mineralocorticoids, glucocorticoids, androgens and estrogens. However, they partly overlap, e.g. mineralocorticoids and glucocorticoids. White circles indicate changes in molecular structure compared with precursors. For more information on interpretation of molecular structures, see structural formula. HSD: Hydroxysteroid dehydrogenase References: Boron WF, Boulpaep EL (2003) Medical Physiology: A Cellular And Molecular Approach, Elsevier/Saunders, pp. page 1,300 ISBN: 1-4160-2328-3. For the absence of conversion of corticosterone to cortisol: Steroid hormone biosynthesis Reference pathway (KO). KEGG: Kyoto Encyclopedia of Genes and Genomes. Kyoto University Bioinformatics Center. (1 November 2013). There is no appreciable conversion of corticosterone to cortisol in the adrenal cortex as 21-OH steroids are poor substrates for 17-alpha hydroxylase. Further reading: Hanukoglu I (1992). “Steroidogenic enzymes: structure, function, and role in regulation of steroid hormone biosynthesis”. The Journal of Steroid Biochemistry and Molecular Biology 43 (8): 779–804. DOI:10.1016/0960-0760(92)90307-5. PMID 22217824. Payne AH, Hales DB (2004). “Overview of steroidogenic enzymes in the pathway from cholesterol to active steroid hormones”. Endocrine Reviews 25 (6): 947–70. DOI:10.1210/er.2003-0030. PMID 15583024. See also: Wikiversity: Diagram of the pathways of human steroidogenesis

The steroidogenic acute regulatory protein, commonly referred to as StAR (STARD1), is a transport protein that regulates cholesterol transfer within the mitochondria, which is the rate-limiting step in the production of steroid hormones. It is primarily present in steroid-producing cells, including theca cells and luteal cells in the ovary, Leydig cells in the testis and cell types in the adrenal cortex.

StAR is a mitochondrial protein that is rapidly synthesized in response to stimulation of the cell to produce steroid. Hormones that stimulate its production depend on the cell type and include luteinizing hormone (LH), ACTH and angiotensin II. At the cellular level, StAR is synthesized typically in response to activation of the cAMP second messenger system, although other systems can be involved even independently of cAMP. StAR has thus far been found in all tissues that can produce steroids, including the adrenal cortex, the gonads, the brain and the nonhuman placenta. One known exception is the human placenta.

Substances that suppress StAR activity, like those listed below, can cause endocrine disrupting effects, including altered steroid hormone levels and fertility.

  1. Alcohol
  2. DEHP and DBP
    • Bis(2-ethylhexyl) phthalate (di-2-ethylhexyl phthalate, diethylhexyl phthalate, diisooctyl phthalate, DEHP; incorrectly — dioctyl phthalate, DIOP) 
    • Dibutyl phthalate (DBP) is an organic compound which is commonly used as a plasticizer because of its low toxicity and wide liquid range. 
  3. Permethrin and cypermethrin
    • Permethrin is a medication and an insecticide. 
    • Cypermethrin (CP) is a synthetic pyrethroid used as an insecticide in large-scale commercial agricultural applications as well as in consumer products for domestic purposes.
  4. DES and arsenite
    • Diethylstilbestrol (DES), also known as stilbestrol or stilboestrol, is a nonsteroidal estrogen medication
  5. BPA

StAR-independent steroidogenesis

While loss of functional StAR in the human and the mouse catastrophically reduces steroid production, it does not eliminate all of it, indicating the existence of StAR-independent pathways for steroid generation. Aside from the human placenta, these pathways are considered minor for endocrine production. It is unclear what factors catalyze StAR-independent steroidogenesis. Candidates include oxysterols which can be freely converted to steroid and the ubiquitous MLN64.

StAR related lipid transfer domain containing 3(STARD3) is a protein that in humans is encoded by the STARD3 gene. STARD3 also known as metastatic lymph node 64 protein (MLN64) is a late endosomalintegral membrane protein involved in cholesterol transport. STARD3 creates membrane contact sites between the endoplasmic reticulum (ER) and late endosomes where it moves cholesterol. This gene encodes a member of a subfamily of lipid trafficking proteins that are characterized by a C-terminal steroidogenic acute regulatory domain and an N-terminal metastatic lymph node 64 domain. The encoded protein localizes to the membranes of late endosomes and may be involved in exporting cholesterol. Alternative splicing results in multiple transcript variants.[provided by RefSeq, Oct 2009]. STARD3 is involved in cholesterol transport from the ER to late endosomes where the protein is anchored. It forms a complex with fellow late endosomal protein STARD3 N-terminal-like protein (STARD3NL) also known as MLN64 N-terminal homologue (MENTHO) and ER VAMP-associated proteins (VAP proteins) A and B (VAP-A, VAP-B) to tether the two organelles together. For STARD3, this interaction is regulated by phosphorylation of a serine in its FFAT motif. The closest homolog to STARD3 is the steroidogenic acute regulatory protein (StAR/StarD1), which initiates the production of steroids by moving cholesterol inside the mitochondrion. Thus, MLN64 is also proposed to move cholesterol inside the mitochondria under certain conditions to initiate StAR-independent steroidogenesis, such as in the human placenta which lacks StAR yet produces steroids. This functional role is supported by evidence that MLN64 expression can stimulate steroid production in a model cell system.

One study indicates that STARD3 (MLN64) also specifically binds lutein in the retina.

STARD3 is a multi-domain protein composed of a N-terminal MENTAL (MLN64 N-terminal) domain, a central phospho-FFAT motif (two phenylalanines in an acidic tract), and a C-terminal StAR-related transfer domain (START) lipid transport domain. The MENTAL domain of STARD3 is similar to the protein STARD3 N-terminal like protein (STARD3NL) also known as MLN64 N-terminal homologue (MENTHO). This domain is composed of 4 transmembrane helices which anchor the protein in the limiting membrane of late endosomes. This domain binds cholesterol and associates with the same domain in STARD3NL. The phospho-FFAT motif is a short protein sequence motif which binds to the ER proteins VAP-A, VAP-B and MOSPD2 proteins after phosphorylation. The START domain of STARD3 is homologous to the StAR protein. X-ray crystallography of the C-terminus indicates that this domain forms a pocket that can bind cholesterol. This places STARD3 within the StarD1/D3 subfamily of START domain-containing proteins.

Tissue distribution (MLN64)

STARD3 is expressed in all tissues in the body at various levels. In the brain, MLN64 is detectable in many but not all cells. Many malignant tumors highly express STARD3 as a result of its gene being part of a Her2/erbB2-containing gene locus that is amplified.

New roles (StAR)

Recent findings suggest that StAR may also traffic cholesterol to a second mitochondrial enzyme, sterol 27-hydroxylase. This enzyme converts cholesterol to 27-hydroxycholesterol. In this way it may be important for the first step in one of the two pathways for the production of bile acids by the liver (the alternative pathway). Evidence also shows that the presence of StAR in a type of immune cell, the macrophage, where it can stimulate the production of 27-hydroxycholesterol. In this case, 27-hydroxycholesterol may by itself be helpful against the production of inflammatory factors associated with cardiovascular disease. It is important to note that no study has yet found a link between the loss of StAR and problems in bile acid production or increased risk for cardiovascular disease. Recently StAR was found to be expressed in cardiac fibroblasts in response to ischemic injury due to myocardial infarction. In these cells it has no apparent de novo steroidogenic activity, as evidenced by the lack of the key steroidogenic enzymes cytochrome P450 side chain cleavage (CYP11A1) and 3 beta hydroxysteroid dehydrogenase (3βHSD). StAR was found to have an anti-apoptotic effect on the fibroblasts, which may allow them to survive the initial stress of the infarct, differentiate and function in tissue repair at the infarction site.

SF-1 has been identified as a transcriptional regulator for an array of different genes related to sex determination and differentiation, reproduction, and metabolism via binding to their promoters. For example, SF-1 controls expression of Amh gene in Sertoli cells, whereby the presence or absence of the gene product affects development of Müllerian structures. Increased AMH protein levels leads to regression of such structures. Leydig cells express SF-1 to regulate transcription of steroidogenesis and testosterone biosynthesis genes causing virilization in males.

Target genes

Steroidogenic cells

First identified as a regulator of steroid hydroxylases within adrenocortical cells, studies aimed to define localization and expression of SF-1 have since revealed enzyme activity within other steroidogenic cells.

speciesGeneCell/Tissue
ratP450sccgranulosa cells
mouseP450sccY1 adrenocortical cells
bovineOxytocinovary
mouseStARMA-10 Leydig cells

Sertoli cells

The Müllerian inhibiting substance (MIS or AMH) gene within Sertoli cells contains a conserved motif identical to the optimal binding sequence for SF-1. Gel mobility shift experiments and use of SF-1-specific polyclonal antibodies established binding complexes of SF-1 to MIS, however, other studies suggest the MIS promoter is repressed and not activated by SF-1 binding.

  • Shen WH, Moore CC, Ikeda Y, Parker KL, Ingraham HA (June 1994). “Nuclear receptor steroidogenic factor 1 regulates the müllerian inhibiting substance gene: a link to the sex determination cascade”. Cell. 77 (5): 651–61. doi:10.1016/0092-8674(94)90050-7. PMID 8205615. S2CID 13364008.

Gonadotropes

Gonadotrope-specific element, or GSE, in the promoter of the gene encoding α-subunit of glycoproteins (α-GSU) resembles the SF-1 binding sires. Studies have implicated SF-1 as an upstream regulator of a collection of genes required for gonadotrope function via GSE.

VMH

SF-1 knockout mice displayed profound defects in the VMH suggesting potential target genes at the site. Target genes have yet to be identified due to difficulties in studying gene expression in neurons.

SF-1 gene knockout

Several approaches used targeted gene disruption in mouse embryonic stem cells with the aim of identifying potential target genes of SF-1. The different targeting strategies include disruption to exons encoding for the zinc finger motif, disruption of a 3’-exon and targeted mutation of the initiator methionine. The corresponding observed phenotypic effects on endocrine development and function were found to be quite similar.

Sf-1 knockout mice displayed diminished corticosterone levels while maintaining elevated ACTH levels. Observed morphological changes and DNA fragmentation was consistent with apoptosis and structural regression resulting in the death of all mice within 8 days after birth.

Sf-1 function was determined to be necessary for development of primary steroidogenic tissue as evidenced by complete lack of adrenal and gonadal glands in the knockout. Male to female sex reversal of genitalia was also observed.

Clinical significance

Mutations in NR5A1 can produce intersex genitals, absence of puberty, and infertility. It is one cause of arrest of ovarian function in women <40 years of age, which occurs in 1% of all women.

Adrenal and gonadal failure

Two SF-1 variants associated with primary adrenal failure and complete gonadal dysgenesis have been reported as caused by NR5A1 mutations. One reported case was found to have de novo heterozygous p.G35E change to the P-box domain. The affected region allows for DNA binding specificity through interactions with regulatory response elements of target genes. This p.G35E change may have a mild competitive or dominant negative effect on transactivation resulting in severe gonadal defects and adrenal dysfunction. Similarly, homozygous p.R92Q change within the A-box interfered with monomeric binding stability and reduced functional activity. This change requires mutations to both allele to display phenotypic effects as heterozygous carriers showed normal adrenal function.

Missense, in-frame and frameshift mutations of NR5A1 have been found in families with 46,XY disorders of sex development, 46,XX gonadal dysgenesis and 46,XX primary ovarian insufficiency. 46,XY individuals may have ambiguous or female genitals. Individuals of either karyotype may not enter puberty, although expression of the phenotype, penetrance, fertility, and modes of inheritance can vary. Some mutations are dominant, some are recessive.

46, XY disorders of sex development

Heterozygous NR5A1 changes are emerging as a frequent contributor in 46, XY complete gonadal dysgenesis. In affected individuals, sexual development does not match their chromosomal makeup. Males, despite having 46, XY karyotype, develop female external genitalia, as well as uterus and fallopian tubes, along with gonadal defects rendering them nonfunctional. NR5A1 mutations have also been linked to partial gonadal dysgenesis, whereby affected individuals have ambiguous genitalia, urogenital sinus, absent or rudimentary Müllerian structures, and other abnormalities.

Typically, these genetic changes are frameshift, nonsense, or missense mutations that alter DNA-binding and gene transcription. While many are de novo, one-third of cases have been maternally inherited in a similar manner as X-linked inheritance. Furthermore, one report of homozygous missense mutation p.D293N within the ligand-binding domain of SF-1 revealed autosomal recessive inheritance was also possible.

Infertility

Analysis of NR5A1 in men with non-obstructive male factor infertility found those with gene changes had more severe forms of infertility and lower testosterone levels. These changes affected the hinge region of SF-1. It is important to note further studies are required to establish the relationship between SF-1 changes and infertility.

Additional interactions

SF-1 has also been shown to interact with:

References

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Further reading

External links

Transcription factors and intracellular receptors
Basic domains
 Zinc finger DNA-binding domains
Helix-turn-helix domains
β-Scaffold factors with minor groove contacts
Other transcription factors
see also transcription factor/coregulator deficiencies
Metabolism: lipid metabolism – ketones/cholesterol synthesis enzymes/steroid metabolism
Cytochromes, oxygenases: cytochrome P450 (Most belong to EC 1.14)
Enzymes: multienzyme complexes
Mitochondrial proteins
Oxidoreductases: CH-NH (EC 1.5)
Enzymes

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