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- Added a few sentences regarding possible underlying genetic causes for infertility .

"Mutations to NR5A1 gene encoding Steroidogenic Factor-1 (SF-1) have been found in a small subset of men with non-obstructive male factor infertility where the cause is unknown. Results of one study investigating a cohort of 315 men revealed changes within the hinge region of SF-1 and no rare allelic variants in fertile control men. Affected individuals displayed more severe forms of infertility such as azoospermia and severe oligozoospermia."

The SF-1 protein is a transcription factor involved in sex determination by controlling activity of genes related to the reproductive glands or gonads and adrenal glands.^[1] 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.^[2]

The NR5A1 gene encodes a 461-amino acid protein that shares several conserved domains consistent with members of the nuclear receptor subfamily.^[2] 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.^[3] 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.^[4]

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

Analysis of mouse SF-1 cDNA revealed sequence similarities with Drosophila fushi tarazu factor I (FTZ-F1) which regulates the fushi tarazu homeobox gene.^[5] 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.^[5]

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.^[2] Leydig cells express SF-1 to regulate transcription of steroidogenesis and testosterone biosynthesis genes causing virilization in males. 

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.^[5] SF-1 specific antibody studies confirmed expression profile of SF-1 in rats^[6] and humans^[7] corresponding to sites of transcript detection.

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.^[8] 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.^[8] 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.

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.^[5]

RT-PCR approaches have detected transcripts of mice FTZ-F1 gene in the placenta and spleen; and SF-1 transcripts in the human placenta.^[9]

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.^[10]

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.^[2]

The Müllerian inhibiting substance (MIS) 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^[11], however, other studies suggest the MIS promoter is repressed and not activated by SF-1 binding. 

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.^[12]

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.

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 zing 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.^[2]

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.^[13]

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. ^[14]

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.^[15] 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.^[15] This change requires mutations to both allele to display phenotypic effects as heterozygous carriers showed normal adrenal function.

Heterozygous NR5A1 changes are emerging as a frequent contributor in 46, XY complete gonadal dysgenesis.^[15] In affected individuals, sexual development does not match their chromosomal makeup. Males, despite having 46, XY karyotype, develop female external genitalia (uterus and fallopian tubes) along with gonadal defects rendering them nonfunctional.^[16] 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.^[15]

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.^[17]

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.^[18] 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.

1. ^ Reference, Genetics Home. "NR5A1 gene". Genetics Home Reference. Retrieved 2017-11-30.
2. ^ ^{a b c d e} Parker, Keith L.; Schimmer, Bernard P. (1997-06-01). "Steroidogenic Factor 1: A Key Determinant of Endocrine Development and Function". Endocrine Reviews. 18 (3): 361–377. doi:10.1210/edrv.18.3.0301. ISSN 0163-769X.
3. ^ Mangelsdorf, D. J.; Thummel, C.; Beato, M.; Herrlich, P.; Schütz, G.; Umesono, K.; Blumberg, B.; Kastner, P.; Mark, M. (1995-12-15). "The nuclear receptor superfamily: the second decade". Cell. 83 (6): 835–839. ISSN 0092-8674. PMID 8521507.
4. ^ Honda, S.; Morohashi, K.; Nomura, M.; Takeya, H.; Kitajima, M.; Omura, T. (1993-04-05). "Ad4BP regulating steroidogenic P-450 gene is a member of steroid hormone receptor superfamily". The Journal of Biological Chemistry. 268 (10): 7494–7502. ISSN 0021-9258. PMID 8463279.
5. ^ ^{a b c d} Ikeda, Y.; Lala, D. S.; Luo, X.; Kim, E.; Moisan, M. P.; Parker, K. L. (July 1993). "Characterization of the mouse FTZ-F1 gene, which encodes a key regulator of steroid hydroxylase gene expression". Molecular Endocrinology (Baltimore, Md.). 7 (7): 852–860. doi:10.1210/mend.7.7.8413309. ISSN 0888-8809. PMID 8413309.
6. ^ Morohashi, K.; Iida, H.; Nomura, M.; Hatano, O.; Honda, S.; Tsukiyama, T.; Niwa, O.; Hara, T.; Takakusu, A. (May 1994). "Functional difference between Ad4BP and ELP, and their distributions in steroidogenic tissues". Molecular Endocrinology (Baltimore, Md.). 8 (5): 643–653. doi:10.1210/mend.8.5.8058072. ISSN 0888-8809. PMID 8058072.
7. ^ Takayama, K.; Sasano, H.; Fukaya, T.; Morohashi, K.; Suzuki, T.; Tamura, M.; Costa, M. J.; Yajima, A. (September 1995). "Immunohistochemical localization of Ad4-binding protein with correlation to steroidogenic enzyme expression in cycling human ovaries and sex cord stromal tumors". The Journal of Clinical Endocrinology and Metabolism. 80 (9): 2815–2821. doi:10.1210/jcem.80.9.7673429. ISSN 0021-972X. PMID 7673429.
8. ^ ^{a b} ""Male Development of Chromosomally Female Mice Transgenic for Sry gene" (1991), by Peter Koopman, et al. | The Embryo Project Encyclopedia". embryo.asu.edu. Retrieved 2017-11-30.
9. ^ Ninomiya, Yasuharu; Okada, Masahiro; Kotomura, Naoe; Suzuki, Katsnyuki; Tsukiyama, Toshio; Niwa, Ohtsura (1995-08-01). "Genomic Organization and Isoforms of the Mouse ELP Gene1". The Journal of Biochemistry. 118 (2): 380–389. doi:10.1093/oxfordjournals.jbchem.a124918. ISSN 0021-924X.
10. ^ Lewis, Aurélia E.; Rusten, Marte; Hoivik, Erling A.; Vikse, Elisabeth L.; Hansson, Magnus L.; Wallberg, Annika E.; Bakke, Marit (2008-1). "Phosphorylation of Steroidogenic Factor 1 Is Mediated by Cyclin-Dependent Kinase 7". Molecular Endocrinology. 22 (1): 91–104. doi:10.1210/me.2006-0478. ISSN 0888-8809. PMC 5419630. PMID 17901130. {{cite journal}}: Check date values in: |date= (help)CS1 maint: PMC format (link)
11. ^ Shen, W. H.; Moore, C. C.; Ikeda, Y.; Parker, K. L.; Ingraham, H. A. (1994-06-03). "Nuclear receptor steroidogenic factor 1 regulates the müllerian inhibiting substance gene: a link to the sex determination cascade". Cell. 77 (5): 651–661. ISSN 0092-8674. PMID 8205615.
12. ^ Ingraham, H. A.; Lala, D. S.; Ikeda, Y.; Luo, X.; Shen, W. H.; Nachtigal, M. W.; Abbud, R.; Nilson, J. H.; Parker, K. L. (1994-10-01). "The nuclear receptor steroidogenic factor 1 acts at multiple levels of the reproductive axis". Genes & Development. 8 (19): 2302–2312. ISSN 0890-9369. PMID 7958897.
13. ^ Luo, X.; Ikeda, Y.; Schlosser, D. A.; Parker, K. L. (September 1995). "Steroidogenic factor 1 is the essential transcript of the mouse Ftz-F1 gene". Molecular Endocrinology (Baltimore, Md.). 9 (9): 1233–1239. doi:10.1210/mend.9.9.7491115. ISSN 0888-8809. PMID 7491115.
14. ^ Luo, X.; Ikeda, Y.; Parker, K. L. (1994-05-20). "A cell-specific nuclear receptor is essential for adrenal and gonadal development and sexual differentiation". Cell. 77 (4): 481–490. ISSN 0092-8674. PMID 8187173.
15. ^ ^{a b c d} Ferraz-de-Souza, Bruno; Lin, Lin; Achermann, John C. (2011-04-10). "Steroidogenic factor-1 (SF-1, NR5A1) and human disease". Molecular and Cellular Endocrinology. 336 (1–2): 198–205. doi:10.1016/j.mce.2010.11.006. ISSN 0303-7207. PMC 3057017. PMID 21078366.{{cite journal}}: CS1 maint: PMC format (link)
16. ^ Reference, Genetics Home. "Swyer syndrome". Genetics Home Reference. Retrieved 2017-11-30.
17. ^ Lourenço, Diana; Brauner, Raja; Lin, Lin; De Perdigo, Arantzazu; Weryha, Georges; Muresan, Mihaela; Boudjenah, Radia; Guerra-Junior, Gil; Maciel-Guerra, Andréa T. (2009-03-19). "Mutations in NR5A1 Associated with Ovarian Insufficiency". New England Journal of Medicine. 360 (12): 1200–1210. doi:10.1056/NEJMoa0806228. ISSN 0028-4793. PMID 19246354.
18. ^ Bashamboo, Anu; Ferraz-de-Souza, Bruno; Lourenço, Diana; Lin, Lin; Sebire, Neil J.; Montjean, Debbie; Bignon-Topalovic, Joelle; Mandelbaum, Jacqueline; Siffroi, Jean-Pierre (2010-10-08). "Human male infertility associated with mutations in NR5A1 encoding steroidogenic factor 1". American Journal of Human Genetics. 87 (4): 505–512. doi:10.1016/j.ajhg.2010.09.009. ISSN 1537-6605. PMC 2948805. PMID 20887963.{{cite journal}}: CS1 maint: PMC format (link)

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