Alternative titles; symbols
HGNC Approved Gene Symbol: NR5A1
Cytogenetic location: 9q33.3 Genomic coordinates (GRCh38): 9:124,481,236-124,507,399 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 9q33.3 | 46XX sex reversal 4 | 617480 | Autosomal dominant | 3 |
| 46XY sex reversal 3 | 612965 | Autosomal dominant | 3 | |
| Adrenocortical insufficiency | 612964 | Autosomal dominant | 3 | |
| Premature ovarian failure 7 | 612964 | Autosomal dominant | 3 | |
| Spermatogenic failure 8 | 613957 | Autosomal dominant | 3 |
NR5A1 is a transcription factor belonging to the nuclear receptor superfamily. It binds the core motif AGGTCA and regulates many genes involved in reproduction, steroidogenesis, and sexual differentiation (summary by Tremblay and Viger, 2003).
Ninomiya et al. (1995) cloned 4 splice variants of mouse Nr5a1, which they called Elp. The 4 variants, Elp1, Elp2, Elp3, and Ad4bp/Sf1, encode 3 isoforms, as Elp3 and Ad4bp/Sf1 have identical coding sequences but differ in their 5-prime noncoding regions. All isoforms contain a DNA-binding domain, a proline-rich region, and region II. Elp2 and Elp3/Ad4bp/Sfl also have region III, which is missing in Elp1. RT-PCR analysis showed complex expression of the variants in mouse tissues, with only embryonal carcinoma cells expression all 4 variants.
Oba et al. (1996) cloned the genomic DNA of the human SF1 gene, the mammalian homolog of Drosophila Ftzf1. They noted that the deduced amino acid sequence of human SF1 consists of 461 amino acids.
By screening an embryonic adrenal gland cDNA library, Wong et al. (1996) cloned human NR5A1, which they called SF1. The deduced 461-amino acid protein contains 2 N-terminal zinc finger DNA-binding domains, followed by an FTZF1 box, a hinge region, a ligand-binding domain, and a C-terminal AF2 transactivation domain. SF2 also has an evolutionarily conserved consensus phosphorylation motif. Human SF2 shares 93 to 95% amino acid identity with cow, rat, and mouse Sf2. The authors noted that mouse Sf2 is alternatively spliced to produce 4 distinct transcripts.
Using immunohistochemistry in rats to analyze NR5A1 expression during steroidogenesis and spermatogenesis, Kojima et al. (2006) observed expression in both Leydig and Sertoli cells in the 7-day-old rat, but expression levels decreased in Sertoli cells by 21 days, and was present only in Leydig cells in the 56-day-old sexually mature rat. In humans, quantitative RT-PCR and Western blot analysis of testicular tissue obtained from males at ages ranging from 1 year to 26 years showed increased expression with increasing age during testicular development. Expression patterns were similar to those seen in rats, with NR5A1 expressed in both Sertoli and Leydig cells in a 1-year-old boy, but showing decreased expression in Sertoli cells in an 8-year-old boy. In pubertal and adult testes NR5A1 was abundantly expressed in the nuclei of Leydig cells, with only a few Sertoli cells showing faint expression. Kojima et al. (2006) concluded that expression of NR5A1 is developmentally regulated, with maximal expression during puberty and high expression after puberty.
Oba et al. (1996) determined that the human SF1 gene spans 30 kb of genomic DNA and is split into 7 exons, including the noncoding first exon.
Wong et al. (1996) determined that the NR5A1 gene contains 7 exons and spans 22 kb.
Taketo et al. (1995) mapped the human NR5A1 gene to chromosome 9q33 by fluorescence in situ hybridization.
By linkage analysis using interspecific backcross mice, Swift and Ashworth (1995) mapped the Nr5a1 gene to mouse chromosome 2. Taketo et al. (1995) further mapped the mouse gene to the proximal quarter of the chromosome.
Luo et al. (1994) reviewed studies implicating SF1 in gonadal differentiation and steroidogenesis. Studies in adrenocortical cells implicated an orphan nuclear receptor, alternatively designated steroidogenic factor-1 (SF1) or adrenal 4-binding protein (AD4BP), in the gene regulation of the 3 enzymes that are required for the biosynthesis of corticosteroids: cholesterol side chain cleavage enzyme (CYP11A1; 118485), steroid 21-hydroxylase (CYP21A2; 613815), and the aldosterone synthase isozyme of steroid 11-beta-hydroxylase (CYP11B2; 124080). Consistent with this postulated role, SF1 in adult mice is expressed in all primary steroidogenic tissues, including the adrenal cortex, testicular Leydig cells, and ovarian theca and granulosa cells and corpus luteum. Furthermore, it is expressed in the urogenital ridge of mouse embryos at embryonic day 9-9.5, the earliest stage of organogenesis of the developing gonads, and is also expressed in fetal Sertoli cells. Structural analysis of an SF1 cDNA showed that it closely matches a mouse cDNA isolated from an embryonal carcinoma cell cDNA library and designated embryonal long terminal repeat-binding protein (ELP) because it binds regulatory elements in retroviral long terminal repeats. Isolation and characterization of genomic clones demonstrated that both SF1 and ELP arose from the same structural gene by alternative promoter usage and splicing. Especially in their shared zinc finger DNA-binding domains, SF1 and ELP closely resembled an orphan nuclear receptor isolated from Drosophila, designated fushi tarazu factor-1, or FTZ-F1 (Lala et al., 1992). For that reason, the mouse gene was designated Ftz-F1. The homologous gene in Drosophila also encodes 2 distinct transcripts proposed to play important roles in Drosophila development.
Shen et al. (1994) proposed that SF1 regulates MIS (600957) in vivo and participates directly in the process of mammalian sex determination. This conclusion was based on several observations. First, in primary Sertoli cells, SF1 regulates the MIS gene by binding to a conserved upstream regulatory element. Second, in heterologous (HeLa) cells, MIS gene activation by SF1 requires removal of the SF1 ligand-binding domain, implicating a Sertoli cell-specific ligand or cofactor. Finally, the sexually dimorphic expression of SF1 during development coincides with MIS expression and mullerian duct regression.
Using transfected NIH3T3 cells, Ninomiya et al. (1995) showed that mouse Elp1 functioned as a transcription repressor, whereas the other Elp isoforms functioned as transactivators.
Nachtigal et al. (1998) showed that WT1(-KTS) (607102) isoforms associate and synergize with SF1 to promote MIS expression. In contrast, WT1 missense mutations, associated with male pseudohermaphroditism in Denys-Drash syndrome (194080), fail to synergize with SF1. Additionally, the X-linked, candidate dosage-sensitive sex-reversal (DSS; 300018) gene, DAX1 (NR0B1; 300473), antagonizes synergy between SF1 and WT1, most likely through a direct interaction with SF1. Nachtigal et al. (1998) proposed that WT1 and DAX1 functionally oppose each other in testis development by modulating SF1-mediated transactivation.
To determine the molecular mechanisms underlying transcriptional regulation of SF1 gene expression in the pituitary, Harris and Mellon (1998) studied a series of deletion and point mutations in the SF1 promoter region for transcriptional activity in alpha-T3-1 and L-beta-T2 (pituitary gonadotrope), CV-1, JEG-3, and Y1 (adrenocortical) cell lines. Their results indicated that maximal expression of the SF1 promoter in all cell types requires an E box element at -82/-77. This E box sequence (CACGTG) is identical to the binding element for upstream stimulatory factor-1 (USF1; 191523), a member of the helix-loop-helix family of transcription factors. Studies of the SF1 gene E box element using gel mobility shift and antibody supershift assays indicated that USF1 may be a key transcriptional regulator of SF1 gene expression.
Hammer et al. (1999) demonstrated that maximal SF1-mediated transcription and interaction with general nuclear receptor cofactors depends on phosphorylation of a single serine residue (ser-203) located in a major activation domain (AF1) of the protein. Moreover, phosphorylation-dependent SF1 activation is likely mediated by the mitogen-activated protein kinase (MAPK) signaling pathway (see 603014). They proposed that this single modification of SF1 and the subsequent recruitment of nuclear receptor cofactors couple extracellular signals to steroid and peptide hormone synthesis, thereby maintaining dynamic homeostatic responses in stress and reproduction. Tremblay et al. (1999) demonstrated that phosphorylation of AF1 by MAPK leads to the recruitment of steroid receptor coactivator-1 (602691) by estrogen receptor-beta (601663) in vitro.
Morohashi (1999) reviewed the gonadal and extragonadal functions of AD4BP/SF1, focusing on the developmental aspects. Gene disruption studies had shown that AD4BP/SF1, originally identified as a steroidogenic tissue-specific transcription factor, plays crucial roles in the process of nonsteroidogenic as well as steroidogenic tissue differentiation. Although the mechanisms underlying differentiation of these tissues were still under investigation, spatial and temporal expression profiles of the AD4BP/SF1 gene supported its contribution to tissue development from the earliest stages of ontogeny.
Gizard et al. (2002) found that coexpression of SF1 and TREP132 (TRERF1; 610322) in an adrenal carcinoma cell line increased CYP11A1 promoter activity, and pull-down, 2-hybrid, and coimmunoprecipitation analyses confirmed SF1-TREP132 interaction. Deletion and mutation analysis showed that the proximal activation domain and AF2 hexamer motif of SF1 interacted with the LxxLL motif in the N-terminal region of TREP132. Coexpression of CBP (CREBBP; 600140)/p300 (EP300; 602700) with SF1 and TREP132 resulted in a synergistic effect on CYP11A1 promoter activity.
Xue et al. (2007) identified a CpG island flanking the SF1 promoter and exon I region (-85/+239) and determined its methylation patterns in endometrial and endometriotic cells. SF1 mRNA and protein levels in endometriotic stromal cells were significantly higher than those in endometrial stromal cells (p less than 0.001). Bisulfite sequencing showed strikingly increased methylation in endometrial cells, compared with endometriotic cells (p less than 0.001). Xue et al. (2007) concluded that this was the first demonstration of methylation-dependent regulation of SF1 in any mammalian tissue and suggested that these findings pointed to a new mechanism for targeting local estrogen biosynthesis in endometriosis (131200).
Sekido and Lovell-Badge (2008) demonstrated that SRY (480000) binds to multiple elements within a Sox9 (608160) gonad-specific enhancer that they called TESCO (testis-specific enhancer of Sox9 core) in mice, and that it does so along with SF1. Mutation, cotransfection, and sex-reversal studies all pointed to a feedforward, self-reinforcing pathway in which SF1 and SRY cooperatively upregulate SOX9; then, together with SF1, SOX9 also binds to the enhancer to help maintain its own expression after that of SRY has ceased. Sekido and Lovell-Badge (2008) concluded that their results permitted further characterization of the molecular mechanisms regulating sex determination, their evolution, and the failure of these mechanisms in cases of sex reversal.
Kojima et al. (2006) analyzed expression levels of NR5A1 mRNA in testicular tissue from 22 patients with nonobstructive azoospermia, and detected NR5A1 in all specimens. Quantitative RT-PCR showed a significant positive correlation between the expression level of NR5A1 and serum testosterone concentration; however, there was no correlation with the severity of histologic pathology observed in the testicular tissue.
Bashamboo et al. (2016) found that in contrast to mouse, where nr5a1 is expressed specifically in the somatic cells of the testis and only trace expression is seen in the early ovary, in human embryos expression of NR5A1 is similar in ovary and testis and higher than in other tissues.
46,XY Sex Reversal 3
Steroidogenic factor-1 is an orphan nuclear receptor that regulates the transcription of an array of genes involved in reproduction, steroidogenesis, and male sexual differentiation, including AMH (600957), DAX1, CYP11A1, steroidogenic acute regulatory protein (STAR; 600617), and those encoding steroid hydroxylases, gonadotropins, and aromatase. Disruption of the Ftzf1 gene in mice causes failure of adrenal and gonadal development, XY sex reversal, persistence of mullerian structures in males, and abnormalities of the hypothalamus and pituitary gonadotropes (see later). In a phenotypically female patient who presented with primary adrenal failure in the first 2 weeks of life and had a 46,XY karyotype (SRXY3; 612965), Achermann et al. (1999) identified heterozygosity for a 2-bp mutation in exon 3 (184757.0001) of the SF1 gene, which encodes part of the DNA-binding domain. By site-directed mutagenesis, Achermann et al. (1999) created the G35E mutant form of SF1 for use in functional studies. The mutation did not interfere with protein translation, stability, or nuclear localization, but it eliminated the binding of SF1 to a canonical binding site. Consistent with its impaired DNA binding, the G35E SF1 mutant did not transactivate a known SF1-responsive reporter gene. The mutant SF1 did not exhibit dominant-negative activity when coexpressed with wildtype SF1. The SF1 mutation in this patient caused complete XY sex reversal, including normal female external genitalia and retention of the uterus. This contrasts with disorders of steroid biosynthesis, in which no uterus is present. The findings provided evidence that SF1 regulates the regression of mullerian structures in humans, either through direct actions on AMH or secondary to an abnormality of Sertoli cell development or function.
Lin et al. (2006) studied the prevalence of DAX1 and SF1 mutations in 117 children and adults with primary adrenal failure of unknown etiology (i.e., not caused by congenital adrenal hyperplasia, adrenoleukodystrophy, or autoimmune disease). SF1 mutations causing adrenal failure were found in only 2 patients with 46,XY gonadal dysgenesis. Lin et al. (2006) concluded that SF1 mutations causing adrenal failure in humans are rare and are more likely to be associated with significant underandrogenization and gonadal dysfunction in 46,XY individuals.
Lin et al. (2007) analyzed the NR5A1 gene in 30 patients with 46,XY disorders of sex development and identified heterozygous missense mutations in 4 patients (184757.0007-184757.0010, respectively). Three of the mutations showed loss of function in adrenal, Leydig, and Sertoli cells lines, but an L437Q ligand-binding domain mutant identified in 1 of the patients (184757.0010) retained partial activity in these cell systems, consistent with the milder clinical phenotype of that patient (hypospadias, male gender assignment).
Kohler et al. (2008) analyzed the NR5A1 gene in 27 German 46,XY patients with severe underandrogenization without adrenal insufficiency and identified heterozygous mutations in 5 (18.5%) patients; the authors concluded that NR5A1 mutations are a relatively frequent cause of 46,XY disorders of sex development.
NR5A1-Related Adrenal Insufficiency
Biason-Lauber and Schoenle (2000) described a female patient with adrenal insufficiency and no apparent defect in ovarian maturation (see 612964), despite a heterozygous mutation in the NR5A1 gene (184757.0002). The authors concluded that NR5A1 has a crucial role in adrenal gland formation in both sexes.
Guran et al. (2016) described a 2-week-old girl with primary adrenal insufficiency, 46,XX karyotype, normal female phenotype, and no evidence of ovarian insufficiency. She carried a homozygous arg92-to-gln mutation in NR5A1 (R92Q; 184757.0003).
Adrenocortical Tumors
Using comparative genomic hybridization, Figueiredo et al. (2005) detected a consistent gain of chromosome 9q or a portion of it in 8 of 9 cases of pediatric adrenocortical tumors (ACTs) and amplification of 9q34 in the majority of these cases. They also examined if the SF1 gene, which is located in this chromosomal region and plays an important role in the development and function of the adrenal cortex, is amplified in these ACT cases. They detected increased copy number of the SF1 gene in all 8 cases with 9q gain, suggesting an association between an increased copy number of the SF1 gene and adrenocortical tumorigenesis.
Premature Ovarian Failure 7
Lourenco et al. (2009) sequenced the NR5A1 gene in 4 families with histories of both 46,XY disorders of sex development and 46,XX primary ovarian insufficiency and in 25 subjects with sporadic ovarian insufficiency. They identified mutations in patients with premature ovarian failure (POF7; 612964) as well as in patients with 46,XY disorders (184757.0011-184757.0016). None of the affected subjects had clinical signs of adrenal insufficiency. In-frame deletions and frameshift and missense mutations were detected. Functional studies indicated that these mutations substantially impaired NR5A1 transactivational activity. None of the mutations were observed in more than 700 control alleles.
Spermatogenic Failure 8
Bashamboo et al. (2010) analyzed the candidate gene NR5A1 in 315 men with idiopathic spermatogenic failure and identified heterozygous missense mutations in 7 of them (see, e.g., 184757.0016-184757.0018). This form of the disorder is designated spermatogenic failure-8 (SPGF8; 613957). None of the mutations were found in more than 2,100 control samples, and analysis of the entire coding region of NR5A1 in 370 fertile men (father of at least 2 children) or 359 normospermic men revealed no rare allelic variants.
46,XX Sex Reversal 4
Using whole-exome, whole-genome, or direct sequencing, Bashamboo et al. (2016) showed that a specific recurrent heterozygous missense mutation, arg92-to-trp (R92W; 184757.0019), in the accessory DNA-binding region of NR5A1 was associated with a variable degree of testis development in 46,XX children and adults from 4 unrelated families (SRXX4; 617480). Remarkably, in 1 family a sib of the proband, raised as a girl and carrying this NR5A1 mutation, was found to have a 46,XY karyotype and partial testicular dysgenesis (SRXY3; 612965). Bashamboo et al. (2016) concluded that these findings highlighted how a specific variant in a developmental transcription factor can switch organ fate from the ovary to testis in mammals, and represented the first missense mutation causing isolated, nonsyndromic 46,XX testicular/ovotesticular DSD in humans.
Baetens et al. (2017) screened a cohort of 11 unrelated cases and 2 sisters with 46,XX SRY-negative (ovo)testicular disorders of sex development (DSD) using whole-exome sequencing in 9 patients, targeted resequencing in 4, and haplotyping. Immunohistochemistry of sex-specific markers was performed on patients' gonads. The consequences of mutation were investigated using luciferase assays, localization studies, and RNA-seq. Baetens et al. (2017) identified a novel heterozygous NR5A1 mutation, c.274C-T (arg92 to trp, R92W; 184757.0019), in 3 unrelated patients. The arg92 residue is highly conserved and located in the Ftz-F1 region, which is thought to be involved in DNA-binding specificity and stability. There were no consistent changes in transcriptional activation or subcellular localization. Transcriptomics in patient-derived lymphocytes showed upregulation of MAMLD1 (300120), a direct NR5A1 target previously associated with 46,XY DSD. In gonads of affected individuals, ovarian FOXL2 (605597) and testicular SRY (480000)-independent SOX9 (608160) expression was observed. Baetens et al. (2017) proposed NR5A1, previously associated with 46,XY DSD and 46,XX primary ovarian insufficiency, as a novel gene for 46,XX (ovo)testicular DSD and hypothesized that the R92W mutation results in decreased inhibition of the male developmental pathway through downregulation of female antitestis genes, thereby tipping the balance toward testicular differentiation in 46,XX individuals. Baetens et al. (2017) concluded that their study supported a role for NR5A1 in testis differentiation in the XX gonad. In the first family reported by Baetens et al. (2017), the proband's healthy sister, father, paternal uncle and grandfather all carried the R92W mutation in NR5A1. A younger sister of the second proband carried the same mutation and displayed normal puberty. In the third family, the proband's 2 younger brothers and mother, all unaffected, carried the R92W mutation. All affected mutation carriers shared a common haplotype spanning a 1.5-Mb region. No other known variants associated with 46,XX sex reversal were identified in any of the probands.
In a 46,XX patient with bilateral ovotestes, Swartz et al. (2017) identified a heterozygous arg92-to-gln (R92Q; 184757.0003) mutation, inherited from the unaffected father. This mutation had previously been reported in a patient with 46,XY DSD (SRXY3; 612965) and in a 46,XX infant with normal female phenotype and adrenal insufficiency (see 612964).
Exclusion Studies
Calvo et al. (2001) used heteroduplex analysis to screen the genes encoding STAR, SF1, DAX1, and CYP11A1 for mutations in genomic DNA from 19 women presenting with hirsutism and increased serum androgen levels. Two variants in the SF1 gene were identified. The authors concluded that mutations in STAR, SF1, CYP11A1, and DAX1 are seldom found in hirsute patients and do not explain the steroidogenic abnormalities found in these women.
To examine the role of Ftzf1 in intact mice, Luo et al. (1994) used targeted disruption of the Ftzf1 gene. Despite normal survival in utero, all Ftzf1-null animals died by postnatal day 8; these animals lacked adrenal glands and gonads and were severely deficient in corticosterone, supporting adrenocortical insufficiency as the probable cause of death. Male and female Ftzf1-null mice had female internal genitalia, despite complete gonadal agenesis. These studies established that the Ftzf1 gene is essential for sexual differentiation and formation of the primary steroidogenic tissues. Normal male sex differentiation requires that Sertoli cells in the embryonic testes produce mullerian-inhibiting substance (AMH; 600957), a TGF-beta-like hormone that causes mullerian duct regression.
Because of the demonstration that reduced expression of steroidogenic factor-1 in patients leads to adrenal failure, Bland et al. (2000) examined SF1 heterozygous mice as a potential model for delineating the mechanisms underlying this disorder. They showed that SF1 +/- mice exhibit adrenal insufficiency resulting from profound defects in adrenal development and organization. However, compensatory mechanisms, such as cellular hypertrophy and increased expression of the rate-limiting steroidogenic protein (600617), help to maintain adrenal function at near normal capacity under basal conditions. In contrast, adrenal deficits in SF1 heterozygotes were revealed under stressful conditions, demonstrating that normal gene dosage of SF1 is required for mounting an adequate stress response. The findings predicted that natural variations leading to reduced SF1 function may underlie some forms of subclinical adrenal insufficiency that become life-threatening during traumatic stress.
Using transgenic mice, Wilhelm and Englert (2002) showed that Wt1(-KTS) binds to 4 promoter sequences of the Sf1 gene, and that Wt1(-KTS) and Lhx9 (606066) have an additive effect in activating the Sf1 promoter. Wt1 was also shown to regulate Dax1 activity in vivo. Gonad development and Dax1 and Sf1 expression were absent in Wt1 mutant mouse embryos.
As the cause of XY sex reversal and adrenal failure in a phenotypically female patient (SRXY3; 612965), Achermann et al. (1999) found a heterozygous 2-bp GGC-to-GAA (glycine-to-glutamic acid; G35E) mutation in exon 3 of the NR5A1 gene. The mutated glycine is the last amino acid in the proximal box (P-box) of the first zinc finger of SF1. This region is critical for the recognition of DNA binding sites and confers specificity to nuclear receptors in the regulation of target genes.
Using mouse and rat constructs, Tremblay and Viger (2003) found that the SF1 G35E mutant bound the promoter region of the MIS gene (AMH; 600957) and interacted normally with its protein coactivator, GATA4 (600576), but that it failed to cooperate with GATA4 to activate the MIS reporter gene. Moreover, SF1 G35E functioned as a dominant-negative competitor and disrupted transcriptional synergism between wildtype SF1 and GATA4.
Biason-Lauber and Schoenle (2000) described a phenotypically normal girl who presented at age 14 months with adrenal insufficiency and no apparent defect in ovarian maturation (see 612964). The authors identified a heterozygous G-to-T transversion in exon 4 of the NR5A1 gene, leading to an arg255-to-leu (R255L) mutation in the hinge region of the NR5A1 protein. There was no evidence of mosaicism.
46,XY Sex Reversal 3
In an infant with adrenal failure and complete 46,XY sex reversal (SRXY3; 612965), Achermann et al. (2002) reported a homozygous G-to-A transition in exon 4 of the NR5A1 gene, which resulted in an arg92-to-gln (R92Q) amino acid change. This mutation altered a highly conserved residue of the A box, a region that functions as a secondary DNA binding domain. Three relatives of the infant (parents and a sister) were phenotypically normal despite being heterozygous for the mutation. In functional assays, the R92Q mutant exhibited partial loss of DNA binding and transcriptional activity when compared with the G35E P-box change (184757.0001), consistent with its phenotypic expression only when transmitted as a homozygous trait.
46,XX Sex Reversal 4
Swartz et al. (2017) reported a 46,XX individual of European ancestry with ambiguous genitalia, including significant clitoromegaly and rugated labia majora (SRXX4; 617480). Ultrasound and MRI showed a small uterus and abdominal gonads that were revealed to be ovotestes bilaterally by histologic analysis. The patient carried a heterozygous R92Q mutation, inherited from her unaffected father.
NR5A1-related Adrenal Insufficiency
In a 2-week-old girl with primary adrenal insufficiency (see 612964) who presented with hyperpigmentation, salt-wasting crisis, prolonged jaundice, hypoglycemia, and vomiting, Guran et al. (2016) detected homozygosity for a R92Q substitution in NR5A1. The karyotype was 46,XX with a normal female phenotype. The family was reported as nonconsanguineous, and the mode of inheritance sporadic.
Correa et al. (2004) reported a novel 8-bp microdeletion of SF1, isolated from a 46,XY patient who presented with gonadal agenesis but normal adrenal function (SRXY3; 612965), that causes premature termination upstream of sequences encoding the activation function-2 domain. In cell transfection experiments, the mutated protein possessed no intrinsic transcriptional activity but rather inhibited the function of the wildtype protein in most cell types. The authors stated that this was the first example of an apparent dominant-negative effect of an SF1 mutation in humans. The authors concluded that these findings, which defined an SF1 mutation that apparently differentially affects its transcriptional activity in vivo in the adrenal cortex and the gonads, may be relevant to patients who present with 46,XY sex reversal but normal adrenal functions.
In a 46,XY patient showing gonadal dysgenesis with normal adrenal function (SRXY3; 612965), Mallet et al. (2004) reported a heterozygous SF1 gene mutation, a C-to-A transversion in exon 2 that replaced cys16 with a stop codon (C16X). The patient showed low basal levels of anti-mullerian hormone (600957) and testosterone (T), weak T response to chorionic gonadotropin (see 118860), and hypoplastic testes with abundant seminiferous tubules but rare germ cells. This mutation caused premature termination of translation and should abolish all SF1 activity; therefore, haploinsufficiency could explain the deleterious effect of this mutation, suggesting that testis development is more SF1 dose-dependent than adrenal development. The authors concluded that heterozygous mutation can impair adrenal development only if the 2 mechanisms, gene dosage and dominant-negative effects, occur.
Hasegawa et al. (2004) identified an SF1 mutation in a 27-year-old Japanese patient with a 46,XY karyotype and complete gonadal dysgenesis (SRXY3; 612965). Sequence analysis of all 7 exons of SF1 revealed a heterozygous 1-bp deletion at exon 2, 18delC, that was predicted to cause a frameshift at codon 6 and result in termination at codon 74 (Asp6fsTer74). Western blot analysis demonstrated no evidence of an amino-truncated SF1 protein despite the 18delC mutation being very close to the natural translation start codon. Transcription analysis indicated that the mutant was transcriptionally inactive and had no dominant-negative effect. Clinical features included small dysgenetic testes with vasa deferentia and epididymides, absent uterus, blind-ending vagina, and clitoromegaly. The authors concluded that SF1 haploinsufficiency can selectively impair testicular development and permit the biosynthesis of AMH (600957) and testosterone in dysgenetic testes and the production of gonadotropins in pituitary gonadotropes.
In a British Caucasian patient with a 46,XY disorder of sex development and normal adrenal function (SRXY3; 612965), Lin et al. (2007) identified heterozygosity for a de novo val15-to-met (V15M) substitution at a highly conserved residue in the first zinc finger of the DNA-binding domain of SF1. The baby was born with female external genitalia, and bilateral gonads (testes) were palpable in rugose labia. Endocrine studies were consistent with gonadal dysgenesis with impaired androgen biosynthesis. Gonadectomy was performed at 4 months of age and the baby was raised female. Neither parent carried the mutation.
In an Italian patient with a 46,XY disorder of sex development and normal adrenal function (SRXY3; 612965), Lin et al. (2007) identified heterozygosity for a met78-to-ile (M78I) substitution in a highly conserved region of SF1 between the DNA-binding zinc fingers and the A-box region. The baby was born with normal female external genitalia, and bilateral gonads (testes) were detectable on deep inguinal palpation. Endocrine investigation showed poor testosterone response to human chorionic gonadotropin stimulation, very low mullerian inhibiting substance, and normal adrenal steroids; the patient underwent gonadectomy at 7 months of age. The mother carried the M78I mutation.
In a Fijian patient with a 46,XY disorder of sex development and normal adrenal function (SRXY3; 612965), Lin et al. (2007) identified heterozygosity for a gly91-to-ser (G91S) substitution in the A-box region of SF1. At birth, clitoral enlargement and a single perineal opening were noted; gonads (testes) were palpable in the labioscrotal folds. Endocrine studies were consistent with gonadal dysgenesis/impaired androgen biosynthesis. Gonadectomy was performed at 4 months of age and the child was raised female. The mother carried the G91S mutation. See 184757.0007 and Lin et al. (2007).
In a British Caucasian patient with a 46,XY disorder of sex development (DSD) and normal adrenal function (SRXY3; 612965), Lin et al. (2007) identified heterozygosity for a de novo leu437-to-gln (L437Q) substitution at a highly conserved residue in the ligand-binding domain of SF1, predicted from the crystal structure to form part of the phospholipid-binding pocket. At birth, a small phallus with severe penoscrotal hypospadias and chordee but moderate corporal tissue were noted; bilateral testes were palpable and could be brought down into the scrotum, although bilateral orchipexy was required at age 6 years. Endocrine studies were consistent with impaired androgen biosynthesis. Evaluation of the hypothalamo-pituitary-gonadal axis in late childhood suggested a partial form of hypogonadotropic hypogonadism in addition to a primary testicular defect, and he required supplemental testosterone to induce puberty. Lin et al. (2007) stated that this was the first reported case of a mild phenotype in a patient raised male, and noted that the L437Q mutant retained partial function in several SF1-expressing cell lines. In contrast, the patient's testicular biopsy at 6 years of age showed more marked changes than those seen in 3 46,XY DSD patients with mutations in the NR5A1 gene (184757.0007-184757.0009) who underwent gonadectomy in infancy.
Lourenco et al. (2009) reported a 17-year-old female with primary amenorrhea who was diagnosed with 46,XY complete gonadal dysgenesis (SRXY3; 612965). Her mother had a history of irregular menstrual cycles and had become pregnant at the age of 23 years. After giving birth, she had anovulatory cycles that were treated for 2 years with no improvement. At age 35, she was diagnosed as 46,XX primary ovarian insufficiency (POF7; 612964). Both the mother and child were heterozygous for a frameshift mutation, 666delC, in codon 225 of the NR5A1 gene, truncating the protein from 461 to 295 amino acids. Functional studies indicated that the mutation substantially impaired NR5A1 transactivational activity. The mutation was not observed in 350 control subjects of European descent.
Lourenco et al. (2009) reported an 18-year-old with primary amenorrhea and signs of virilization who was diagnosed with a 46,XY disorder of sex development (SRXY3; 612965). A sister of the proband presented at the age of 19 years with primary amenorrhea and the diagnosis of 46,XX primary ovarian insufficiency (POF7; 612964). Mutation analysis in both sibs revealed homozygosity for an 877G-A transition in the NR5A1 gene, resulting in an asp293-to-asn (D293N) substitution. The parents were first cousins. DNA and hormonal studies were performed on 5 of 8 fertile sibs of the proband; 4 of the sibs were heterozygous and a brother did not carry the mutation. Further investigation of the family revealed a female family member with 46,XY complete gonadal dysgenesis but DNA was not available for study; her parents were also first cousins. Functional studies indicated that the mutation substantially impaired NR5A1 transactivational activity. The mutation was not observed in 782 control subjects from throughout the world.
Lourenco et al. (2009) reported a French child who presented at the age of 12 years with signs of virilization and was diagnosed with 46,XY partial gonadal dysgenesis (SRXY3; 612965). A sister of the proband presented at the age of 16 years with secondary amenorrhea and was diagnosed with 46,XX primary ovarian insufficiency (POF7; 612964). The mother was 46 years of age, and menstruation was reportedly normal. The 2 affected sibs and the mother carried a heterozygous 3G-A transition in the first codon of the NR5A1 gene that predicts a met1-to-ile (M1I) substitution. Functional studies indicated that the mutation substantially impaired NR5A1 transactivational activity. An unaffected sib and the father did not have the mutation. The mutation was not found in 350 unaffected French control subjects.
Lourenco et al. (2009) reported a French child with ambiguous external genitalia and a 46,XY karyotype who was diagnosed with a disorder of sex development (SRXY3; 612965) and was raised as a boy. After his birth, his mother took oral contraceptives for 2 years until she was 29 years old, after which her menstrual cycles did not reappear. Her diagnosis was 46,XX primary ovarian insufficiency (POF7; 612964). A heterozygous frameshift mutation, 390delG, was detected in the NR5A1 gene in both the proband and his mother. The mutation is predicted to create a premature termination at codon 295. Functional studies indicated that the mutation substantially impaired NR5A1 transactivational activity. The mutation was not detected in 350 unaffected French control subjects.
Lourenco et al. (2009) reported a girl of Roma origin who presented at 12.5 years with short stature and a 46,XX karyotype. She was diagnosed with ovarian failure (POF7; 612964). Analysis of the NR5A1 gene revealed a heterozygous in-frame 9-bp deletion (691_699delCTGCAGCTG) that results in the loss of 3 amino acids (leu231_leu233) in the N-terminal region of the ligand-binding domain. In silico analysis predicted a change in hydrophobicity of helix 1 of the ligand-binding domain. Functional studies indicated that the mutation substantially impaired NR5A1 transactivational activity. The deletion was not observed in 800 control alleles, including samples from 69 unaffected subjects of Roma origin and 56 unaffected subjects from an Indian Gujarati population.
In a 4-month-old girl of Senegalese origin who presented with hypertrophy of the clitoris, Lourenco et al. (2009) found elevated FSH, indicating ovarian insufficiency (POF7; 612964). Molecular analysis identified 2 mutations in the NR5A1 gene that occurred in cis: a 368G-C transversion resulting in a gly123-to-ala (G123A) substitution, and a 386C-T transition resulting in a pro129-to-leu (P129L) substitution. Both mutations occurred in the hinge domain of the protein. The parents were not available for study. Functional studies indicated that the mutations substantially impaired NR5A1 transactivational activity. Neither mutation was found in 479 unaffected control subjects.
In 2 Congolese men with azoospermia and 1 Tunisian man with severe oligospermia (SPGF8; 613957), Bashamboo et al. (2010) identified heterozygosity for the cis-occurring G123A/P129L mutations in the NR5A1 gene. The authors noted that all of the individuals reported to carry this double mutation were of African origin, suggesting that this is likely a founder mutation. One of the men carrying this mutation was observed to have progressive loss of germ cell quantity and quality over a 2-year period.
In a 41-year-old Sri Lankan man with azoospermia (SPGF8; 613957), Bashamboo et al. (2010) identified heterozygosity for a 392C-T transition in the NR5A1 gene, resulting in a pro131-to-leu substitution within the hinge region of the protein. The mutation was not found in more than 2,100 control samples, in 370 fertile men who had fathered at least 2 children, or in 359 normospermic men. Functional studies in HEK293T cells demonstrated a greater than 60% reduction in transactivation of the promoters of 2 NR5A1 target genes, CYP11A1 (118485) and AMH (600957), compared to wildtype.
In a 37-year-old French-Vietnamese man with severe oligozoospermia (SPGF8; 613957), Bashamboo et al. (2010) identified heterozygosity for a 634G-A transition in the NR5A1 gene, resulting in a gly212-to-ser (G212S) substitution within the hinge region of the protein. The mutation was not found in more than 2,100 control samples, in 370 fertile men who had fathered at least 2 children, or in 359 normospermic men. Functional studies in HEK293T cells demonstrated approximately 80% and 70% reductions in transactivation of the promoters of 2 NR5A1 target genes, CYP11A1 (118485) and AMH (600957), respectively, compared to wildtype.
In 5 patients from 4 unrelated families with 46,XX sex reversal (SRXX4; 617480), Bashamboo et al. (2016) identified a c.274C-T transition in the NR5A1 gene that resulted in an arg-to-trp substitution at codon 92 (R92W). In 1 of these families, a sister had 46,XY sex reversal (SRXY3; 612965) due to the same variant. In 2 families, the variant was maternally inherited, in 1 it occurred as a de novo event, and in 1 family the mutation was not present in the father, but the mother was deceased and no DNA was available. The variant was absent from the dbSNP (build 138), ExAC, and 1000 Genomes Project databases, and from an internal database containing exomes of 400 individuals as well as more than 1,000 fertile controls Sanger sequenced for NR5A1. The arg92 residue in NR5A1 is evolutionarily conserved to zebrafish.
In 3 unrelated probands with 46,XX (ovo)testicular disorder of sexual development (DSD), Baetens et al. (2017) found a c.274C-T transition in exon 4 of the NR5A1 gene (c.274C-T, NM_004959.4) that resulted in an R92W substitution in the protein. Several unaffected female first-degree relatives of the probands from each of the families also carried this mutation, suggesting that this variant is weakly penetrant. A potential founder effect was suggested by haplotype analysis. The arg92 residue is highly evolutionarily conserved to zebrafish and located in the Ftz-F1 region, probably involved with DNA-binding specificity and stability. The R92W mutation was absent from the Exome Sequencing Project (ESP), ExAC, Genome of the Netherlands (GoNL), and 1000 Genomes Project databases and from an in-house exome database.
Igarashi et al. (2017) identified the R92W mutation (c.274C-T, NM_004959.4) in 2 unrelated Japanese patients with 46,XX testicular/ovotesticular DSD. The mutation was absent from the clinically normal mothers and from 200 Japanese controls. One of the fathers, who was unaffected, carried the mutation; the other father was not available for analysis. In vitro assays showed that the mutant protein was less sensitive than wildtype to NR0B1 (300473)-induced suppression on the SOX9 (608160) enhancer element.
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