Species: mouse
Mutation name: None
type: null mutation
fertility: infertile - ovarian defect
Comment: Analyses of knockout mice lacking SF-1 by gene targeting disruption demonstrated that SF-1 disrupted mice lack adrenal glands and gonads, supporting the suggestion that SF-1 is an essential regulatior of the endocrine development and differentiation (Ikeda, 1996) . Impaired Follicle Development and Infertility in Female Mice Lacking Steroidogenic Factor 1 in Ovarian Granulosa Cells. Pelusi C et al. The nuclear receptor steroidogenic factor 1 (SF-1, NR5A1) is essential for fetal gonadal development, but its roles in postnatal ovarian function are less well defined. Here, we have extended our analyses of knockout (KO) mice with markedly decreased SF-1 expression in granulosa cells. As described, these SF-1 KO mice had hypoplastic ovaries that contained a decreased number of follicles and lacked corpora lutea. In this study, we showed that the SF-1 KO mice exhibited abnormal estrous cycles, were infertile, and released significantly fewer oocytes in response to a standard superovulation regimen. Moreover, they had a blunted induction of plasma estradiol in response to gonadotropins. The granulosa cell-specific SF-1 KO also significantly affected ovarian expression of putative SF-1 target genes. Consistent with their decreased follicle number, these mice had reduced ovarian expression of anti-m?an hormone (Amh), which correlates with the reserve pool of ovarian follicles, and decreased gonadotropin-induced ovarian expression of aromatase (Cyp19a1) and cyclin-D2 (Ccnd2). In contrast, perhaps due to their abnormal cyclicity, SF-1 KO ovaries had higher basal expression of inhibin-alpha. They also had decreased immunoreactivity for genes related to proliferation (Ccnd2 and Mki67, also known as Ki67) and increased expression of Cdkn1b, also known as p27, which inhibits cyclin-dependent kinases, arguing for a role of SF-1 in granulosa cell proliferation. These studies demonstrate that SF-1 plays a key role in female reproduction via essential actions in granulosa cells.

Species: mouse
Mutation name: None
type: null mutation
fertility: infertile - ovarian defect
Comment: Cell-specific Knockout of Steroidogenic Factor 1 Reveals Its Essential Roles in Gonadal Function. Jeyasuria P, et al . Knockout mice lacking the orphan nuclear receptor steroidogenic factor 1 (SF-1, officially designated Nr5a1) have a compound endocrine phenotype that includes adrenal and gonadal agenesis, impaired expression of pituitary gonadotropins, and structural abnormalities of the ventromedial hypothalamic nucleus. To inactivate a conditional SF-1 allele in the gonads, we targeted the expression of Cre recombinase with a knock-in allele of the anti-Mullerian hormone type 2 receptor (Amhr2) locus. In testes, Cre was expressed in Leydig cells. The testes of adult gonad-specific SF-1 KO mice remained at the level of the bladder and were markedly hypoplastic, due at least partly to impaired spermatogenesis. Histological abnormalities of the testes were seen from early developmental stages and were associated with markedly decreased Leydig cell expression of two essential components of testosterone biosynthesis, Cyp11a and the steroidogenic acute regulatory protein (StAR). In females, the Amhr2-cre allele directed Cre expression to granulosa cells. Although wild-type and SF-1 KO ovaries were indistinguishable during embryogenesis and at birth, adult females were sterile and their ovaries lacked corpora lutea and contained hemorrhagic cysts resembling those in estrogen receptor alpha and aromatase KO mice. Collectively, these studies establish definitively that SF-1 expression in the gonads is essential for normal reproductive development and function.

Species: human
Mutation name: None
type: naturally occurring
fertility: infertile - ovarian defect
Comment: Steroidogenic factor-1 (SF-1) gene mutation as a frequent cause of primary amenorrhea in 46,XY female adolescents with low testosterone concentration. Philibert P et al. ABSTRACT: BACKGROUND: Primary amenorrhea due to 46,XY disorders of sex differentiation (DSD) is a frequent reason for consultation in endocrine and gynecology clinics. Among the genetic causes of low-testosterone primary amenorrhea due to 46,XY DSD, SRY gene is reported to be frequently involved, but other genes, such as SF1 and WT1, have never been studied for their prevalence. METHODS: We directly sequenced SRY, SF1 and WT1 genes in 15 adolescent girls with primary amenorrhea, low testosterone concentration, and XY karyotype, to determine the prevalence of mutations. We also analyzed the LH receptor gene in patients with high LH and normal FSH concentrations. RESULTS: Among the 15 adolescents with primary amenorrhea and low testosterone concentration, we identified two new SRY mutations, five new SF1 mutations and one new LH receptor gene mutation. Our study confirms the 10-15% prevalence of SRY mutations and shows the high prevalence (33%) of SF1 abnormalities in primary amenorrhea due to 46,XY DSD with low plasma testosterone concentration. CONCLUSIONS: The genetic analysis of low-testosterone primary amenorrhea is complex as several factors may be involved. This work underlines the need to systematically analyze the SF1 sequence in girls with primary amenorrhea due to 46,XY DSD and low testosterone, as well as in newborns with 46,XY DSD.

Species: human
Mutation name: None
type: naturally occurring
fertility: subfertile
Comment: Screening and familial characterization of copy-number variations in NR5A1 in 46,XY disorders of sex development and premature ovarian failure. Harrison SM 2013 et al. The NR5A1 gene encodes for steroidogenic factor 1, a nuclear receptor that regulates proper adrenal and gonadal development and function. Mutations identified by NR5A1 sequencing have been associated with disorders of sex development (DSD), ranging from sex reversal to severe hypospadias in 46,XY patients and premature ovarian failure (POF) in 46,XX patients. Previous reports have identified four families with a history of both 46,XY DSD and 46,XX POF carrying segregating NR5A1 sequence mutations. Recently, three 46,XY DSD sporadic cases with NR5A1 microdeletions have been reported. Here, we identify the first NR5A1 microdeletion transmitted in a pedigree with both 46,XY DSD and 46,XX POF. A 46,XY individual with DSD due to gonadal dysgenesis was born to a young mother who developed POF. Array CGH analysis revealed a maternally inherited 0.23?Mb microdeletion of chromosome 9q33.3, including the NR5A1 gene. Based on this finding, we screened patients with unexplained 46,XY DSD (n?=?11), proximal hypospadias (n?=?21) and 46,XX POF (n?=?36) for possible NR5A1 copy-number variations (CNVs) via multiplex ligation-dependent probe amplification (MLPA), but did not identify any additional CNVs involving NR5A1. These data suggest that NR5A1 CNVs are an infrequent cause of these disorders but that array CGH and MLPA are useful genomic screening tools to uncover the genetic basis of such unexplained cases. This case is the first report of a familial NR5A1 CNV transmitting in a pedigree, causing both the male and female phenotypes associated with NR5A1 mutations, and the first report of a NR5A1 CNV associated with POF. /////////////////////////

Species: human
Mutation name:
type: naturally occurring
fertility: fertile
Comment: Clinical follow-up of the first SF-1 insufficient female patient. Gerster K et al. (2017) Steroidogenic factor 1 (SF-1/NR5A1) plays a crucial role in regulating adrenal development, gonad determination and differentiation, and in the hypothalamic-pituitary control of reproduction and metabolism. In men (46, XY), it is known that mutations in SF-1/NR5A1 gene cause a wide phenotypic spectrum with variable degrees of undervirilization. In recent years, the role of SF-1 in the ovarian function was increasingly discussed and alterations in the gene were related to primary ovarian insufficiency. We describe the follow-up of a 46, XX affected woman with a SF-1 mutation and by comparing our case with the known manifestations reported in the literature, we try to further elucidate the function of SF-1 in the ovary. During infancy, adrenal insufficiency was the only clinical sign of the loss-of-function as ovarian development and function seemed normal. To date, this young woman aged 16.5 years shows normal growth, normal BMI and psychomotor development, has a normal puberty and regular menstruation. This report shows one, to date uniquely described, phenotypic variant of SF-1 mutation in a 46, XX affected person with adrenocortical insufficiency but no ovarian dysfunction nor disturbance of pubertal development. To follow the natural history of SF-1 mutation in a 46, XX individual will further shed light on its role in the ovarian function and thus will help to counsel affected patients in future.//////////////////

Species: human
Mutation name: Sex reversal , XY, with adrenal failure [NR5A1, GLY35GLU]
type: naturally occurring
fertility: unknown
Comment: As the cause of XY sex reversal and adrenal failure in a phenotypically female patient, 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.