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1
Shi, Boyang, Huijie Lu, Lihong Zhang e Weimin Zhang. "Nr5a1b promotes and Nr5a2 inhibits transcription of lhb in the orange-spotted grouper, Epinephelus coioides†". Biology of Reproduction 101, n. 4 (17 luglio 2019): 800–812. http://dx.doi.org/10.1093/biolre/ioz121.
Abstract (sommario):
Abstract Nr5a1 (Sf-1) up-regulates lhb expression across vertebrates; however, its regulatory roles on fshb remain to be defined. Moreover, the involvement of Nr5a2 in the regulation of gonadotropin expression is not clear either. In the present study, the involvement of Nr5a1b (a homologue of Nr5a1) and Nr5a2 in the regulation of lhb and fshb expression in the orange-spotted grouper was examined. Dual fluorescent immunohistochemistry using homologous antisera showed that in the pituitary of orange-spotted groupers, Lh cells contain both immunoreactive Nr5a1b and Nr5a2 signals, whereas Fsh cells contain neither of them. In LβT2 cells, Nr5a1b up-regulated basal activities of lhb and fshb promoters possibly via Nr5a sites, and synergistically (on lhb promoter) or additively (on fshb promoter) with forskolin. Surprisingly, Nr5a2 inhibited basal activities of lhb promoter possibly via Nr5a sites and attenuated the stimulatory effects of both forskolin and Nr5a1b. In contrast, Nr5a2 had no effects on fshb promoter. Chromatin immunoprecipitation analysis showed that both Nr5a1b and Nr5a2 bound to lhb promoter, but not fshb promoter in the pituitary of the orange-spotted grouper. The abundance of Nr5a1b bound to lhb promoter was significantly higher at the vitellogenic stage than the pre-vitellogenic stage, whereas that of Nr5a2 exhibited an opposite trend. Taken together, data of the present study demonstrated antagonistic effects of Nr5a1b and Nr5a2 on lhb transcription in the orange-spotted grouper and revealed novel regulatory mechanisms of differential expression of lhb and fshb genes through Nr5a homologues in vertebrates.
2
KUO, Ming-Wei, John POSTLETHWAIT, Wen-Chih LEE, Show-Wan LOU, Woon-Khiong CHAN e Bon-chu CHUNG. "Gene duplication, gene loss and evolution of expression domains in the vertebrate nuclear receptor NR5A (Ftz-F1) family". Biochemical Journal 389, n. 1 (21 giugno 2005): 19–26. http://dx.doi.org/10.1042/bj20050005.
Abstract (sommario):
Fushi tarazu factor 1 (Ftz-F1, NR5A) is a zinc-finger transcription factor that belongs to the nuclear receptor superfamily and regulates genes that are involved in sterol and steroid metabolism in gonads, adrenals, liver and other tissues. To understand the evolutionary origins and developmental genetic relationships of the Ftz-F1 genes, we have cloned four homologous Ftz-f1 genes in zebrafish, called ff1a, ff1b, ff1c and ff1d. These four genes have different temporal and spatial expression patterns during development, indicating that they have distinct mechanisms of genetic regulation. Among them, the ff1a expression pattern is similar to mammalian Nr5a2, while the ff1b pattern is similar to that of mammalian Nr5a1. Genetic mapping experiments show that these four ff1 genes are located on chromosome segments conserved between the zebrafish and human genomes, indicating a common ancestral origin. Phylogenetic and conserved synteny analysis show that ff1a is the orthologue of NR5A2, and that ff1b and ff1d genes are co-orthologues of NR5A1 that arose by a gene-duplication event, probably a whole-genome duplication, in the ray-fin lineage, and each gene is located next to an NR6A1 co-orthologue as in humans, showing that the tandem duplication occurred before the divergence of human and zebrafish lineages. ff1c does not have a mammalian counterpart. Thus we have characterized the phylogenetic relationships, expression patterns and chromosomal locations of these Ftz-F1 genes, and have demonstrated their identities as NR5A genes in relation to the orthologous genes in other species.
3
Suyama, Atsuhito, Nahoko Iwata, Yoshiaki Soejima, Yasuhiro Nakano, Koichiro Yamamoto, Takahiro Nada e Fumio Otsuka. "Involvement of NR5A1 and NR5A2 in the Regulation of Steroidogenesis by Clock Gene and BMPs by Human Granulosa Cells". Journal of the Endocrine Society 5, Supplement_1 (1 maggio 2021): A768. http://dx.doi.org/10.1210/jendso/bvab048.1562.
Abstract (sommario):
Abstract We previously reported that the expression levels of Clock gene are linked to the expression levels of steroidogenetic enzymes in human granulosa cells (EJ 2019). However, the downstream molecules of the Clock gene actions in the regulation of ovarian steroidogenesis have yet to be elucidated. In the present study, we investigated the roles of the transcription factors, NR5A1 (also known as SF-1) and NR5A2 (LRH-1), which play key roles in the reproductive function as well as steroidogenesis by focusing on the functional link between Clock gene and bone morphogenetic protein (BMP) signaling using human granulosa KGN cells. First of all, we examined the effects of BMPs/growth differentiation factor (GDF) on forskolin (FSK)-induced steroidogenesis. As a result, FSK-induced mRNA levels of StAR and P450scc, but not P450arom, were potently suppressed by treatments with BMP-6, -9, -15 and GDF-9. The expression levels of NR5A1 and NR5A2 mRNA were also upregulated by FSK treatment, while the BMP-target gene Id-1 mRNA levels were stimulated by the treatment with BMPs. Of interest, treatments with BMPs/GDF increased FSK-induced NR5A1 mRNA levels but suppressed FSK-induced NR5A2 mRNA levels by granulosa cells. The expression levels of NR5A1 mRNA were positively correlated with the changes of P450arom and 3βHSD mRNA, whereas the expression levels of NR5A2 mRNA were correlated with that of StAR and P450scc mRNA. In addition, the expression levels of NR5A1 and NR5A2 mRNAs were positively correlated with the levels of Clock mRNA. In particular, Clock mRNA levels showed highly positive correlation with the levels of NR5A2 mRNA compared with NR5A1 mRNA. Of note, Id-1 mRNA levels were positively correlated with the levels of NR5A1 mRNA, but negatively correlated with that of NR5A2 mRNA. Furthermore, the inhibition of Clock gene expression by siRNA attenuated the expression levels of NR5A1 and NR5A2 mRNA, resulting in decreased mRNA levels of StAR and P450arom in the presence of FSK. Thus, the present results suggested a novel mechanism by which Clock expression is functionally linked to the expression of NR5A1 and NR5A2, the latter of which is further regulated by BMP signaling by granulosa cells. The interaction among Clock, NR5A1/NR5A2 and BMPs may be involved in the fine tuning of steroidogenesis by ovarian follicles.
4
Suzuki, Taiga, Megumi Kasahara, Hidefumi Yoshioka, Ken-ichirou Morohashi e Kazuhiko Umesono. "LXXLL-Related Motifs in Dax-1 Have Target Specificity for the Orphan Nuclear Receptors Ad4BP/SF-1 and LRH-1". Molecular and Cellular Biology 23, n. 1 (1 gennaio 2003): 238–49. http://dx.doi.org/10.1128/mcb.23.1.238-249.2003.
Abstract (sommario):
ABSTRACT The orphan receptor Ad4BP/SF-1 (NR5A1) is a constitutive activator, and its activity is repressed by another orphan receptor, Dax-1 (NR0B1). In the present study, we investigated the molecular mechanisms underlying this repression by Dax-1. Yeast two-hybrid and transient-transfection assays confirmed the necessity of three LXXLL-related motifs in Dax-1 for interaction with and repression of Ad4BP/SF-1. In vitro pull-down experiments confirmed that Dax-1 interacts with Ad4BP/SF-1 and also with LRH-1 (NR5A2). The target specificity of the LXXLL-related motifs was indicated by the observations that Ad4BP/SF-1, ERα (NR3A1), LRH-1, ERR2 (NR3B2), and fly FTZ-F1 (NR5A3) interacted through their ligand binding domains with all the LXXLL-related motifs in Dax-1 whereas HNF4 (NR2A1) and RORα (NR1F1) did not. Transcriptional activities of the receptors whose DNA binding domains (DBDs) were replaced by the GAL4 DBD were repressed by Dax-1 to various levels, which correlated with the strength of interaction. Amino acid substitutions revealed that Ad4BP/SF-1 and LRH-1 preferentially interact with L(+1)XXLL-related motifs containing serine, tyrosine, serine, and threonine at positions −2, +2, +3, and +6, respectively. Taken together, our results indicate that the specificities of LXXLL-related motifs in Dax-1 based on their amino acid sequences play an important role in regulation of orphan receptors.
5
Martin, Luc J., e Jacques J. Tremblay. "Glucocorticoids antagonize cAMP-induced Star transcription in Leydig cells through the orphan nuclear receptor NR4A1". Journal of Molecular Endocrinology 41, n. 3 (1 luglio 2008): 165–75. http://dx.doi.org/10.1677/jme-07-0145.
Abstract (sommario):
It is well established that stress, either physical or psychosocial, causes a decrease in testosterone production by Leydig cells. Glucocorticoids (Gc) are the main mediators of stress response and they convey their repressive effect on Leydig cells through the glucocorticoid receptor (GR). So far, various mechanisms have been proposed to explain the mechanism of action of Gc on Leydig cell steroidogenesis including repression of genes involved in testosterone biosynthesis. Several steroidogenic genes, including steroidogenic acute regulatory (STAR) protein, have been shown to be repressed by Gc in a GR-dependent manner but the underlying mechanisms remain to be fully elucidated. Here, we found that dexamethasone (Dex), a potent synthetic Gc, partly antagonizes the cAMP-dependent stimulation of the mouse Star promoter in MA-10 Leydig cells as revealed by transient transfection assays. This repression requires an element located at −95 bp previously implicated in the activation of the Star promoter by the nuclear receptors, NR4A1 and NR5A1. Dex was found to inhibit NR4A1-dependent transactivation of the Star promoter in Leydig cells by decreasing NR4A1, but not NR5A1, recruitment to the proximal Star promoter as determined by chromatin immunoprecipitation assay. Western blots revealed that Dex did not affect NR4A1 or NR5A1 expression in response to cAMP. These data suggest that NR4A1 would be associated with the GR in a transcriptionally inactive complex as previously demonstrated in pituitary corticotrope cells. Thus, our data provide new molecular insights into the stress-mediated suppression of testosterone production in testicular Leydig cells.
6
Emura, Natsuko, Chiung-Min Wang, William Harry Yang e Wei-Hsiung Yang. "Steroidogenic Factor 1 (NR5A1) Activates ATF3 Transcriptional Activity". International Journal of Molecular Sciences 21, n. 4 (20 febbraio 2020): 1429. http://dx.doi.org/10.3390/ijms21041429.
Abstract (sommario):
Steroidogenic Factor 1 (SF-1/NR5A1), an orphan nuclear receptor, is important for sexual differentiation and the development of multiple endocrine organs, as well as cell proliferation in cancer cells. Activating transcription factor 3 (ATF3) is a transcriptional repressor, and its expression is rapidly induced by DNA damage and oncogenic stimuli. Since both NR5A1 and ATF3 can regulate and cooperate with several transcription factors, we hypothesized that NR5A1 may interact with ATF3 and plays a functional role in cancer development. First, we found that NR5A1 physically interacts with ATF3. We further demonstrated that ATF3 expression is up-regulated by NR5A1. Moreover, the promoter activity of the ATF3 is activated by NR5A1 in a dose-dependent manner in several cell lines. By mapping the ATF3 promoter as well as the site-directed mutagenesis analysis, we provide evidence that NR5A1 response elements (−695 bp and −665 bp) are required for ATF3 expression by NR5A1. It is well known that the transcriptional activities of NR5A1 are modulated by post-translational modifications, such as small ubiquitin-related modifier (SUMO) modification and phosphorylation. Notably, we found that both SUMOylation and phosphorylation of NR5A1 play roles, at least in part, for NR5A1-mediated ATF3 expression. Overall, our results provide the first evidence of a novel relationship between NR5A1 and ATF3.
7
Morohashi, Ken-ichirou, Miki Inoue e Takashi Baba. "Coordination of Multiple Cellular Processes by NR5A1/Nr5a1". Endocrinology and Metabolism 35, n. 4 (31 dicembre 2020): 756–64. http://dx.doi.org/10.3803/enm.2020.402.
8
Luppino, Giovanni, Malgorzata Wasniewska, Roberto Coco, Giorgia Pepe, Letteria Anna Morabito, Alessandra Li Pomi, Domenico Corica e Tommaso Aversa. "Role of NR5A1 Gene Mutations in Disorders of Sex Development: Molecular and Clinical Features". Current Issues in Molecular Biology 46, n. 5 (9 maggio 2024): 4519–32. http://dx.doi.org/10.3390/cimb46050274.
Abstract (sommario):
Disorders/differences of sex development (DSDs) are defined as broad, heterogenous groups of congenital conditions characterized by atypical development of genetic, gonadal, or phenotypic sex accompanied by abnormal development of internal and/or external genitalia. NR5A1 gene mutation is one of the principal genetic alterations implicated in causing DSD. This review outlines the role of NR5A1 gene during the process of gonadal development in humans, provides an overview of the molecular and functional characteristics of NR5A1 gene, and discusses potential clinical phenotypes and additional organ diseases due to NR5A1 mutations. NR5A1 mutations were analyzed in patients with 46,XY DSD and 46,XX DSD both during the neonatal and pubertal periods. Loss of function of the NR5A1 gene causes several different phenotypes, including some associated with disease in additional organs. Clinical phenotypes may vary, even among patients carrying the same NR5A1 variant, indicating that there is no specific genotype–phenotype correlation. Genetic tests are crucial diagnostic tools that should be used early in the diagnostic pathway, as early as the neonatal period, when gonadal dysgenesis is the main manifestation of NR5A1 mutation. NR5A1 gene mutations could be mainly associated with amenorrhea, ovarian failure, hypogonadism, and infertility during puberty. Fertility preservation techniques should be considered as early as possible.
9
Domenice, Sorahia, Aline Zamboni Machado, Frederico Moraes Ferreira, Bruno Ferraz‐de‐Souza, Antonio Marcondes Lerario, Lin Lin, Mirian Yumie Nishi et al. "Wide spectrum of NR5A1‐related phenotypes in 46,XY and 46,XX individuals". Birth Defects Research Part C: Embryo Today: Reviews 108, n. 4 (dicembre 2016): 309–20. http://dx.doi.org/10.1002/bdrc.21145.
Abstract (sommario):
Steroidogenic factor 1 (NR5A1, SF‐1, Ad4BP) is a transcriptional regulator of genes involved in adrenal and gonadal development and function. Mutations in NR5A1 have been among the most frequently identified genetic causes of gonadal development disorders and are associated with a wide phenotypic spectrum. In 46,XY individuals, NR5A1‐related phenotypes may range from disorders of sex development (DSD) to oligo/azoospermia, and in 46,XX individuals, from 46,XX ovotesticular and testicular DSD to primary ovarian insufficiency (POI). The most common 46,XY phenotype is atypical or female external genitalia with clitoromegaly, palpable gonads, and absence of Müllerian derivatives. Notably, an undervirilized external genitalia is frequently seen at birth, while spontaneous virilization may occur later, at puberty. In 46,XX individuals, NR5A1 mutations are a rare genetic cause of POI, manifesting as primary or secondary amenorrhea, infertility, hypoestrogenism, and elevated gonadotropin levels. Mothers and sisters of 46,XY DSD patients carrying heterozygous NR5A1 mutations may develop POI, and therefore require appropriate counseling. Moreover, the recurrent heterozygous p.Arg92Trp NR5A1 mutation is associated with variable degrees of testis development in 46,XX patients. A clear genotype‐phenotype correlation is not seen in patients bearing NR5A1 mutations, suggesting that genetic modifiers, such as pathogenic variants in other testis/ovarian‐determining genes, may contribute to the phenotypic expression. Here, we review the published literature on NR5A1‐related disease, and discuss our findings at a single tertiary center in Brazil, including ten novel NR5A1 mutations identified in 46,XY DSD patients. The ever‐expanding phenotypic range associated with NR5A1 variants in XY and XX individuals confirms its pivotal role in reproductive biology, and should alert clinicians to the possibility of NR5A1 defects in a variety of phenotypes presenting with gonadal dysfunction. Birth Defects Research (Part C) 108:309–320, 2016. © 2016 The Authors Birth Defects Research Part C: Embryo Today: Reviews Published by Wiley Periodicals, Inc.
10
Shima, Yuichi, Kanako Miyabayashi, Takami Mori, Koji Ono, Mizuki Kajimoto, Hae Lim Cho, Hitomi Tsuchida et al. "Intronic Enhancer Is Essential for Nr5a1 Expression in The Pituitary Gonadotrope and for Postnatal Development of Male Reproductive Organs in a Mouse Model". International Journal of Molecular Sciences 24, n. 1 (22 dicembre 2022): 192. http://dx.doi.org/10.3390/ijms24010192.
Abstract (sommario):
Nuclear receptor subfamily 5 group A member 1 (NR5A1) is expressed in the pituitary gonadotrope and regulates their differentiation. Although several regulatory regions were implicated in Nr5a1 gene expression in the pituitary gland, none of these regions have been verified using mouse models. Furthermore, the molecular functions of NR5A1 in the pituitary gonadotrope have not been fully elucidated. In the present study, we generated mice lacking the pituitary enhancer located in the 6th intron of the Nr5a1 gene. These mice showed pituitary gland-specific disappearance of NR5A1, confirming the functional importance of the enhancer. Enhancer-deleted male mice demonstrated no defects at fetal stages. Meanwhile, androgen production decreased markedly in adult, and postnatal development of reproductive organs, such as the seminal vesicle, prostate, and penis was severely impaired. We further performed transcriptomic analyses of the whole pituitary gland of the enhancer-deleted mice and controls, as well as gonadotropes isolated from Ad4BP-BAC-EGFP mice. These analyses identified several genes showing gonadotrope-specific, NR5A1-dependent expressions, such as Spp1, Tgfbr3l, Grem1, and Nr0b2. These factors are thought to function downstream of NR5A1 and play important roles in reproductive organ development through regulation of pituitary gonadotrope functions.
11
Martínez de LaPiscina, Idoia, Rana AA Mahmoud, Kay-Sara Sauter, Isabel Esteva, Milagros Alonso, Ines Costa, Jose Manuel Rial-Rodriguez et al. "Variants of STAR, AMH and ZFPM2/FOG2 May Contribute towards the Broad Phenotype Observed in 46,XY DSD Patients with Heterozygous Variants of NR5A1". International Journal of Molecular Sciences 21, n. 22 (13 novembre 2020): 8554. http://dx.doi.org/10.3390/ijms21228554.
Abstract (sommario):
Variants of NR5A1 are often found in individuals with 46,XY disorders of sex development (DSD) and manifest with a very broad spectrum of clinical characteristics and variable sex hormone levels. Such complex phenotypic expression can be due to the inheritance of additional genetic hits in DSD-associated genes that modify sex determination, differentiation and organ function in patients with heterozygous NR5A1 variants. Here we describe the clinical, biochemical and genetic features of a series of seven patients harboring monoallelic variants in the NR5A1 gene. We tested the transactivation activity of novel NR5A1 variants. We additionally included six of these patients in a targeted diagnostic gene panel for DSD and identified a second genetic hit in known DSD-causing genes STAR, AMH and ZFPM2/FOG2 in three individuals. Our study increases the number of NR5A1 variants related to 46,XY DSD and supports the hypothesis that a digenic mode of inheritance may contribute towards the broad spectrum of phenotypes observed in individuals with a heterozygous NR5A1 variation.
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Tanaka, Tomoko, Chikao Aoyagi, Toshihiko Yanase e Shohta Kodama. "ODP045 Implantation of Steroidogenic Cells Derived from Human Adipose-derived Stem Cells Extends Survival in a Mouse Model of Adrenal Insufficiency". Journal of the Endocrine Society 6, Supplement_1 (1 novembre 2022): A60. http://dx.doi.org/10.1210/jendso/bvac150.124.
Abstract (sommario):
Abstract Cell therapy has an advantage of compensating hormone in response to physiological stimuli. We have previously shown that mouse mesenchymal stem cells (MSCs) were transformed into steroidogenic cells by forced expression of NR5A1 (a master regulator of steroidogenesis, also known as SF-1/Ad4BP) and that the syngeneic implantation of NR5A1-induced steroidogenic cells extended survival of bilateral adrenoectomised (bAdx) mice. However, ACTH receptor is not induced by NR5A1 in mouse MSCs, and ACTH responsiveness was not detected in recipient mice. In contrast to mice, in human MSCs, ACTH receptor is induced by NR5A1 and ACTH enhances steroid production in NR5A1 induced-steroidogenic cells in vitro studies. In the present study, we implanted human ADSCs-derived steroidogenic cells into immunodeficient mice with adrenal insufficiency. Human adipose tissue-derived stem cells (ADSCs) were inoculated with recombinant adenovirus containing human NR5A1 or LacZ cDNA (MOI=50) and cultured for 7 days. NR5A1 induced-steroidogenic cells secreted both adrenal and gonadal steroids and responded to ACTH. Before xenotransplantation studies, adrenal glands of SCID/Beige mice were surgically removed and implanted into under capsule of the kidney. bAdx mice were dead within 9 days (N=11), bAdx mice (N=12) transplanted with adrenal glands survived to the endpoint of 30 days, and died within 9 days after removal of the kidney containing the graft. We next implanted NR5A1-induced steroidogenic cells or control cells into bAdx mice. The overall survival rate (endpoint of 30 days) of NR5A1 implanted mice was 16.7%, (N=12) while control cell implanted mice died within 13 days (N=10). Median survival time of bAdx mice implanted with NR5A1 induced-steroidogenic cells and control ADSCs was 16. 0 and 11. 0 days, respectively (log-rank test, p < 0. 0001). In the NR5A1 induced-steroidogenic cells implanted mice, serum aldosterone was undetectable, whereas serum corticosterone and cortisol were detectable. Although we performed ACTH loading test on bAdx mice implanted with NR5A1-induced steroidogenic cells, no ACTH responsiveness was detected. The expression of Pomc mRNA in the pituitary gland was increased by bAdx, whereas this increase was not suppressed by implantation of steroid-producing cells (N=3), suggesting that the amount of steroids in the graft complemented survival but was insufficient for negative feedback. These results indicate that human ADSCs are transformed into steroidogenic cells by NR5A1 and are responsive to ACTH in vitro but not in vivo. Xenotransplantation of the induced steroidogenic cells into immunodeficient bAdx mice prolonged the survival, which was supported by the significant detection of basal serum corticosterone and cortisol levels. In particular, serum cortisol indicated hormone secretion from the grafts, suggesting that human ADSCs may also be useful as a regenerative source of steroid-producing cells. Presentation: No date and time listed
13
Tantawy, Sally, Inas Mazen, Hala Soliman, Ghada Anwar, Abeer Atef, Mona El-Gammal, Ahmed El-Kotoury et al. "Analysis of the gene coding for steroidogenic factor 1 (SF1, NR5A1) in a cohort of 50 Egyptian patients with 46,XY disorders of sex development". European Journal of Endocrinology 170, n. 5 (maggio 2014): 759–67. http://dx.doi.org/10.1530/eje-13-0965.
Abstract (sommario):
ObjectiveSteroidogenic factor 1 (SF1, NR5A1) is a key transcriptional regulator of genes involved in the hypothalamic–pituitary–gonadal axis. Recently, SF1 mutations were found to be a frequent cause of 46,XY disorders of sex development (DSD) in humans. We investigate the frequency of NR5A1 mutations in an Egyptian cohort of XY DSD.DesignClinical assessment, endocrine evaluation and genetic analysis of 50 Egyptian XY DSD patients (without adrenal insufficiency) with a wide phenotypic spectrum.MethodsMolecular analysis of NR5A1 gene by direct sequencing followed by in vitro functional analysis of the two novel missense mutations detected.ResultsThree novel heterozygous mutations of the coding region in patients with hypospadias were detected. p.Glu121AlafsX25 results in severely truncated protein, p.Arg62Cys lies in DNA-binding zinc finger, whereas p.Ala154Thr lies in the hinge region of SF1 protein. Transactivation assays using reporter constructs carrying promoters of anti-Müllerian hormone (AMH), CYP11A1 and TESCO core enhancer of Sox9 showed that p.Ala154Thr and p.Arg62Cys mutations result in aberrant biological activity of NR5A1. A total of 17 patients (34%) harboured the p.Gly146Ala polymorphism.ConclusionWe identified two novel NR5A1 mutations showing impaired function in 23 Egyptian XY DSD patients with hypospadias (8.5%). This is the first study searching for NR5A1 mutations in oriental patients from the Middle East and Arab region with XY DSD and no adrenal insufficiency, revealing a frequency similar to that in European patients (6.5–15%). We recommend screening of NR5A1 in patients with hypospadias and gonadal dysgenesis. Yearly follow-ups of gonadal function and early cryoconservation of sperms should be performed in XY DSD patients with NR5A1 mutations given the risk of future fertility problems due to early gonadal failure.
14
Faienza, Maria F., Mariangela Chiarito, Fulvia Baldinotti, Domenico Canale, Carmela Savino, Guglielmo Paradies, Domenico Corica et al. "NR5A1 Gene Variants: Variable Phenotypes, New Variants, Different Outcomes". Sexual Development 13, n. 5-6 (2019): 258–63. http://dx.doi.org/10.1159/000507411.
Abstract (sommario):
<i>NR5A1</i> (nuclear receptor subfamily 5 group A member 1) is a transcriptional regulator of adrenal and gonadal development and function. Heterozygous and homozygous <i>NR5A1 </i>mutations have been described in people with 46,XY disorders of sex development (DSD). The clinical, endocrine, and genetic features of four 46,XY subjects with <i>NR5A1</i> genetic variants (2 sisters, 2 boys) from 3 unrelated families are reported. All subjects presented with hypergonadotropic hypogonadism and abnormal pubertal progression. Markers of Sertoli cell function were more affected than those of Leydig cell function. Genetic investigation demonstrated the presence of different heterozygous <i>NR5A1</i> genetic variants. In the boys, pathogenetic<i> NR5A1</i> gene variants were found that had been previously reported. The 2 sisters carried a new genetic variant in exon 4, and in silico analysis and ACMG classification indicated its pathogenicity. The data confirmed that <i>NR5A1 </i>gene mutations may present with variable genital phenotypes. Anyway, reproductive function was always impaired. Any clinical or endocrine data seem to be unable to differentiate these patients from other 46,XY DSD cases, suggesting that molecular analysis must be warranted. In subjects with <i>NR5A1</i> mutations, different decisions in sex assignment may permit satisfying somatic and psychological outcome, but any option requires hormonal substitutive therapy from adolescence onward.
15
Sakai, Noriko, Hiromi Terami, Shinobu Suzuki, Megumi Haga, Ken Nomoto, Nobuko Tsuchida, Ken-ichirou Morohashi et al. "Identification of NR5A1 (SF-1/AD4BP) gene expression modulators by large-scale gain and loss of function studies". Journal of Endocrinology 198, n. 3 (25 giugno 2008): 489–97. http://dx.doi.org/10.1677/joe-08-0027.
Abstract (sommario):
Nuclear receptor subfamily 5, group A, member 1 (NR5A1 previously known as SF-1/AD4BP) is a transcription factor involved in the development of adrenal/gonadal tissues and steroidogenic linage cell differentiation in adult somatic stem cells. To understand the cellular signaling network that regulates NR5A1 gene expression, loss of function screening with an siRNA kinome library, and gain of function screening with an addressable full-length cDNA library representing one quarter of the human genome was carried out. The NR5A1 gene expression was activated in mesenchymal stem cells by siRNA directed against protein kinase C (PKC)-δ, erb-B3, RhoGAP (ARHGAP26), and hexokinase 2, none of which were previously known to be involved in the NR5A1 gene expression. Among these, we identified crosstalk between erb-B3 and PKC-δ signaling cascades. In addition, the gain of function studies indicated that sex-determining region Y (SRY)-box 15 (SOX15), TEA domain family member 4, KIAA1257 (a gene of unknown function), ADAM metallopeptidase with thrombospondin type 1 motif 6, Josephin domain containing 1, centromere protein, TATA box-binding protein-associated factor 5-like RNA polymerase, and inducible T-cell co-stimulator activate NR5A1 gene expression. These results provide new insights into the molecular mechanisms of NR5A1 gene expression.
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Martinez de Lapiscina, Idoia, Chrysanthi Kouri, Josu Aurrekoetxea, Mirian Sanchez, Rawda Naamneh Elzenaty, Kay-Sara Sauter, Núria Camats et al. "Genetic reanalysis of patients with a difference of sex development carrying the NR5A1/SF-1 variant p.Gly146Ala has discovered other likely disease-causing variations". PLOS ONE 18, n. 7 (11 luglio 2023): e0287515. http://dx.doi.org/10.1371/journal.pone.0287515.
Abstract (sommario):
NR5A1/SF-1 (Steroidogenic factor-1) variants may cause mild to severe differences of sex development (DSD) or may be found in healthy carriers. The NR5A1/SF-1 c.437G>C/p.Gly146Ala variant is common in individuals with a DSD and has been suggested to act as a susceptibility factor for adrenal disease or cryptorchidism. Since the allele frequency is high in the general population, and the functional testing of the p.Gly146Ala variant revealed inconclusive results, the disease-causing effect of this variant has been questioned. However, a role as a disease modifier is still possible given that oligogenic inheritance has been described in patients with NR5A1/SF-1 variants. Therefore, we performed next generation sequencing (NGS) in 13 DSD individuals harboring the NR5A1/SF-1 p.Gly146Ala variant to search for other DSD-causing variants and clarify the function of this variant for the phenotype of the carriers. Panel and whole-exome sequencing was performed, and data were analyzed with a filtering algorithm for detecting variants in NR5A1- and DSD-related genes. The phenotype of the studied individuals ranged from scrotal hypospadias and ambiguous genitalia in 46,XY DSD to opposite sex in both 46,XY and 46,XX. In nine subjects we identified either a clearly pathogenic DSD gene variant (e.g. in AR) or one to four potentially deleterious variants that likely explain the observed phenotype alone (e.g. in FGFR3, CHD7). Our study shows that most individuals carrying the NR5A1/SF-1 p.Gly146Ala variant, harbor at least one other deleterious gene variant which can explain the DSD phenotype. This finding confirms that the NR5A1/SF-1 p.Gly146Ala variant may not contribute to the pathogenesis of DSD and qualifies as a benign polymorphism. Thus, individuals, in whom the NR5A1/SF-1 p.Gly146Ala gene variant has been identified as the underlying genetic cause for their DSD in the past, should be re-evaluated with a NGS method to reveal the real genetic diagnosis.
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Camats, N., A. V. Pandey, M. Fernández-Cancio, P. Andaluz, M. Janner, N. Torán, F. Moreno et al. "Ten Novel Mutations in the NR5A1 Gene Cause Disordered Sex Development in 46,XY and Ovarian Insufficiency in 46,XX Individuals". Journal of Clinical Endocrinology & Metabolism 97, n. 7 (1 luglio 2012): E1294—E1306. http://dx.doi.org/10.1210/jc.2011-3169.
Abstract (sommario):
Abstract Context: Steroidogenic factor-1 (SF-1/NR5A1) is a nuclear receptor that regulates adrenal and reproductive development and function. NR5A1 mutations have been detected in 46,XY individuals with disorders of sexual development (DSD) but apparently normal adrenal function and in 46,XX women with normal sexual development yet primary ovarian insufficiency (POI). Objective: A group of 100 46,XY DSD and two POI was studied for NR5A1 mutations and their impact. Design: Clinical, biochemical, histological, genetic, and functional characteristics of the patients with NR5A1 mutations are reported. Setting: Patients were referred from different centers in Spain, Switzerland, and Turkey. Histological and genetic studies were performed in Barcelona, Spain. In vitro studies were performed in Bern, Switzerland. Patients: A total of 65 Spanish and 35 Turkish patients with 46,XY DSD and two Swiss 46,XX patients with POI were investigated. Main Outcome: Ten novel heterozygote NR5A1 mutations were detected and characterized (five missense, one nonsense, three frameshift mutations, and one duplication). Results: The novel NR5A1 mutations were tested in vitro by promoter transactivation assays showing grossly reduced activity for mutations in the DNA binding domain and variably reduced activity for other mutations. Dominant negative effect of the mutations was excluded. We found high variability and thus no apparent genotype-structure-function-phenotype correlation. Histological studies of testes revealed vacuolization of Leydig cells due to fat accumulation. Conclusions: SF-1/NR5A1 mutations are frequently found in 46,XY DSD individuals (9%) and manifest with a broad phenotype. Testes histology is characteristic for fat accumulation and degeneration over time, similar to findings observed in patients with lipoid congenital adrenal hyperplasia (due to StAR mutations). Genotype-structure-function-phenotype correlation remains elusive.
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Kato, Tomoko, Michiyo Esaki, Ayami Matsuzawa e Yayoi Ikeda. "NR5A1 is required for functional maturation of Sertoli cells during postnatal development". REPRODUCTION 143, n. 5 (maggio 2012): 663–72. http://dx.doi.org/10.1530/rep-11-0365.
Abstract (sommario):
The orphan nuclear receptor steroidogenic factor 1 (NR5A1 (SF-1)) is expressed in both Sertoli and Leydig cells in the testes. This study investigates the postnatal development of the testes of a gonad-specific Nr5a1 knockout (KO) mouse, in which Nr5a1 was specifically inactivated. The KO testes appeared histologically normal from postnatal day 0 (P0) until P7. However, disorganized germ cells, vacuoles, and giant cells appeared by P14 in the seminiferous tubules of KO but not control mice. Expression of NR5A1 and various factors was examined by immunohistochemistry (IHC). The number of NR5A1-positive Sertoli cells in the KO testes was lower compared with controls at all the developmental stages and decreased to nearly undetectable levels by P21. IHC for anti-Müllerian hormone and p27, immature and mature Sertoli cell markers, respectively, indicated a delay in Sertoli cell maturation in the KO testes. The number of Sertoli cell-expressing factors involved in Sertoli cell differentiation including WT1, SOX9, GATA4, and androgen receptor were lower in the KO testes compared with controls. Furthermore, fewer proliferating cell nuclear antigen-positive proliferative germ cells were observed, and the number of TUNEL-labeled cells was significantly higher in the KO testes compared with controls at P14 and P21, indicating impaired spermatogenesis. IHC for CYP11A1 (SCC) indicated the presence of steroidogenic Leydig cells in the interstitium of the KO testes at all stages examined. These results suggest that NR5A1 is essential for Sertoli cell maturation and therefore spermatogenesis, during postnatal testis development.
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Köhler, Birgit, Lin Lin, Inas Mazen, Cigdem Cetindag, Heike Biebermann, Ilker Akkurt, Rainer Rossi, Olaf Hiort, Annette Grüters e John C. Achermann. "The spectrum of phenotypes associated with mutations in steroidogenic factor 1 (SF-1, NR5A1, Ad4BP) includes severe penoscrotal hypospadias in 46,XY males without adrenal insufficiency". European Journal of Endocrinology 161, n. 2 (agosto 2009): 237–42. http://dx.doi.org/10.1530/eje-09-0067.
Abstract (sommario):
ObjectiveHypospadias is a frequent congenital anomaly but in most cases an underlying cause is not found. Steroidogenic factor 1 (SF-1, NR5A1, Ad4BP) is a key regulator of human sex development and an increasing number of SF-1 (NR5A1) mutations are reported in 46,XY disorders of sex development (DSD). We hypothesized that NR5A1 mutations could be identified in boys with hypospadias.Design and methodsMutational analysis of NR5A1 in 60 individuals with varying degrees of hypospadias from the German DSD network.ResultsHeterozygous NR5A1 mutations were found in three out of 60 cases. These three individuals represented the most severe end of the spectrum studied as they presented with penoscrotal hypospadias, variable androgenization of the phallus and undescended testes (three out of 20 cases (15%) with this phenotype). Testosterone was low in all three patients and inhibin B/anti-Müllerian hormone (AMH) were low in two patients. Two patients had a clear male gender assignment. Gender re-assignment to male occurred in the third case. Two patients harbored heterozygous nonsense mutations (p.Q107X/WT, p.E11X/WT). One patient had a heterozygous splice site mutation in intron 2 (c.103-3A/WT) predicted to disrupt the main DNA-binding motif. Functional studies of the nonsense mutants showed impaired transcriptional activation of an SF-1-responsive promoter (Cyp11a). To date, adrenal insufficiency has not occurred in any of the patients.ConclusionsSF-1 (NR5A1) mutations should be considered in 46,XY individuals with severe (penoscrotal) hypospadias, especially if undescended testes, low testosterone, or low inhibin B/AMH levels are present. SF-1 mutations in milder forms of idiopathic hypospadias are unlikely to be common.
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Kherouatou-Chaoui, Naouel, Djalila Chellat-Rezgoune, Mohamed Larbi Rezgoune, Ken Mc Elreavey, Laaldja Souhem Touabti, Noreddine Abadi e Dalila Satta. "SRY and NR5A1 gene mutation in Algerian children and adolescents with DSD and testicular dysgenesis". African Health Sciences 21, n. 3 (27 settembre 2021): 1491–97. http://dx.doi.org/10.4314/ahs.v21i3.61.
Abstract (sommario):
Background: In humans, sex determination and differentiation is genetically controlled. Disorders of sex development (DSD) result in anomalies of the development of the external and internal genitalia. Variants in transcription factors such as SRY, NR5A1 and SOX9, can cause changes in gonadal development often associated with ambiguity of the external genitalia.
Objectives: This study has been conducted to determine the frequency, types and associated genetic alterations in patients with DSD in the Algerian population.
Methods: Thirty patients were included. Based on their clinical presentation, thirteen patients presented with ambiguous external genitalia, thirteen patients presented with hypospadias and four patients presented with bilateral undescended tes- tes. Karyotype analysis was performed on peripheral blood lymphocytes using standard R-banding. DNA was isolated from blood leukocytes for PCR reaction and mutational analysis of SRY and NR5A1 was done by direct sequencing.
Results: Most patients with ambiguous genitalia had a 46,XY karyotype. One patient had a deletion of SRY, otherwise no point mutations in SRY or NR5A1 genes were identified. However, a single NR5A1 polymorphism (p.Gly146Ala) in patient with 46,XX DSD has been detected.
Conclusions: The absence of mutations in these genes suggests that there are others genes playing an important role in sex development and differentiation.
Keywords: DSD; consanguinity; karyotyping; SRY; NR5A1; sequencing.
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Orekhova, Anna S., Natalia Kalinchenko, Ivan A. Morozov, Evgeny V. Vasilyev, Petr M. Rubtsov, Ivan I. Dedov e Anatoly Tiulpakov. "A Novel Mutation in the Critical P-Box Residue of Steroidogenic Factor-1 Presenting with XY Sex Reversal and Transient Adrenal Failure". Hormone Research in Paediatrics 89, n. 6 (17 novembre 2017): 450–54. http://dx.doi.org/10.1159/000481776.
Abstract (sommario):
Background: Although the importance of steroidogenic factor-1 (SF1, NR5A1) for adrenal development is supported by numerous in vitro and in vivo studies, cases of SF1 deficiency associated with adrenal failure are exceptionally rare. The first human NR5A1 mutation was a heterozygous de novo p.G35E variant identified in a patient with disorder of sex development (DSD) 46,XY and primary adrenal insufficiency. Here we describe another association of the “classic” SF1 phenotype with a novel NR5A1 mutation affecting G35 residue. Methods: We describe the clinical characteristics of a phenotypically female patient presenting at 2 months with signs of adrenal insufficiency. DSD 46,XY was diagnosed at 4 years. The NR5A1 gene was analyzed by Sanger sequencing. Minigene splicing and dual luciferase reporter assays were used to characterize effects of the novel mutation on splicing and transcription, respectively. Results: Sequencing of the NR5A1 gene revealed a de novo heterozygous c.104G>A:p.G35D substitution. The minigene experiments demonstrated that c.104G>A substitution did not affect splicing. However, transactivation activity of the p.G35D mutant was clearly impaired, which was comparable with the effect of the p.G35E mutation. Conclusions: The findings stress the importance of G35 residue for adrenal development. The current observation also suggests that some patients with SF1 deficiency may present with transient adrenal failure.
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Piprek, Rafal P., Izabela Rams-Pociecha, Robert Zdanowski, Malgorzata Kloc e Jacek Z. Kubiak. "Desmoplakin (Dsp) conditional knockout in NR5A1+ somatic cells affects germ cell survival in developing mouse gonads". Reproduction 163, n. 4 (1 aprile 2022): 199–207. http://dx.doi.org/10.1530/rep-21-0295.
Abstract (sommario):
Cell to cell interactions are crucial for morphogenesis and tissue formation. Desmoplakin (encoded by the Dsp gene) is a component of desmosomes and anchors the transmembrane adhesion proteins to the cytoskeleton. Its role in gonad development remains vague. To study the role of desmoplakin in gonad development, we used a tissue-specific knockout of the Dsp gene in the NR5A1+ somatic cells of the gonads. We show here that desmoplakin is necessary for the survival of germ cells in fetal testes and ovaries. The Dspknockout in NR5A1+ somatic cells in testes decreased the number of germ cells, and thus the size of the testes, but did not affect the Sertoli cells or the structure of testis cords and interstitium. The Dspknockout in NR5A1+ somatic cells in ovaries decreased the number of female germ cells and drastically reduced the formation of ovarian follicles. Dsp knockout in NR5A1+ somatic cells did not affect the sex determination and sexual differentiation of the gonads, as judged from an unchanged expression of genes essential for these processes. We conclude that mediation by desmoplakin cell adhesion between the gonadal cells is necessary for germ cell survival.
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Hattori, Atsushi, e Maki Fukami. "Nuclear Receptor Gene Variants Underlying Disorders/Differences of Sex Development through Abnormal Testicular Development". Biomolecules 13, n. 4 (19 aprile 2023): 691. http://dx.doi.org/10.3390/biom13040691.
Abstract (sommario):
Gonadal development is the first step in human reproduction. Aberrant gonadal development during the fetal period is a major cause of disorders/differences of sex development (DSD). To date, pathogenic variants of three nuclear receptor genes (NR5A1, NR0B1, and NR2F2) have been reported to cause DSD via atypical testicular development. In this review article, we describe the clinical significance of the NR5A1 variants as the cause of DSD and introduce novel findings from recent studies. NR5A1 variants are associated with 46,XY DSD and 46,XX testicular/ovotesticular DSD. Notably, both 46,XX DSD and 46,XY DSD caused by the NR5A1 variants show remarkable phenotypic variability, to which digenic/oligogenic inheritances potentially contribute. Additionally, we discuss the roles of NR0B1 and NR2F2 in the etiology of DSD. NR0B1 acts as an anti-testicular gene. Duplications containing NR0B1 result in 46,XY DSD, whereas deletions encompassing NR0B1 can underlie 46,XX testicular/ovotesticular DSD. NR2F2 has recently been reported as a causative gene for 46,XX testicular/ovotesticular DSD and possibly for 46,XY DSD, although the role of NR2F2 in gonadal development is unclear. The knowledge about these three nuclear receptors provides novel insights into the molecular networks involved in the gonadal development in human fetuses.
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Meinsohn, Marie-Charlotte, Olivia E. Smith, Kalyne Bertolin e Bruce D. Murphy. "The Orphan Nuclear Receptors Steroidogenic Factor-1 and Liver Receptor Homolog-1: Structure, Regulation, and Essential Roles in Mammalian Reproduction". Physiological Reviews 99, n. 2 (1 aprile 2019): 1249–79. http://dx.doi.org/10.1152/physrev.00019.2018.
Abstract (sommario):
Nuclear receptors are intracellular proteins that act as transcription factors. Proteins with classic nuclear receptor domain structure lacking identified signaling ligands are designated orphan nuclear receptors. Two of these, steroidogenic factor-1 (NR5A1, also known as SF-1) and liver receptor homolog-1 (NR5A2, also known as LRH-1), bind to the same DNA sequences, with different and nonoverlapping effects on targets. Endogenous regulation of both is achieved predominantly by cofactor interactions. SF-1 is expressed primarily in steroidogenic tissues, LRH-1 in tissues of endodermal origin and the gonads. Both receptors modulate cholesterol homeostasis, steroidogenesis, tissue-specific cell proliferation, and stem cell pluripotency. LRH-1 is essential for development beyond gastrulation and SF-1 for genesis of the adrenal, sexual differentiation, and Leydig cell function. Ovary-specific depletion of SF-1 disrupts follicle development, while LRH-1 depletion prevents ovulation, cumulus expansion, and luteinization. Uterine depletion of LRH-1 compromises decidualization and pregnancy. In humans, SF-1 is present in endometriotic tissue, where it regulates estrogen synthesis. SF-1 is underexpressed in ovarian cancer cells and overexpressed in Leydig cell tumors. In breast cancer cells, proliferation, migration and invasion, and chemotherapy resistance are regulated by LRH-1. In conclusion, the NR5A orphan nuclear receptors are nonredundant factors that are crucial regulators of a panoply of biological processes, across multiple reproductive tissues.
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Wei, Xianzhen, Shan Li e Yu He. "NR5A1-related 46,XY partial gonadal dysgenesis: A case report and literature review". Medicine 102, n. 52 (29 dicembre 2023): e36725. http://dx.doi.org/10.1097/md.0000000000036725.
Abstract (sommario):
Rationale: Disorders/differences of sex development (DSD) include a diverse group of congenital conditions in which the development of chromosomal, gonadal, or anatomical sex is discordant. It involves several variant genes, and one of them is NR5A1. NR5A1 encodes a signal transduction regulator in the hypothalamic-pituitary-gonadal and hypothalamic-pituitary-adrenal pathway, and pathogenic mutation in this gene is a cause of 46,XY DSD. Patient concerns: A 12-year-old individual raised as a girl was admitted to the hospital due to hirsutism and a deep voice that began at 11 years old. The individual exhibited testicular hypoplasia, clitoral hypertrophy, and female external genitalia. Diagnoses: The patient was diagnosed 46,XY partial gonadal dysgenesis. The cytogenetics revealed a 46,XY karyotype and DNA sequencing shown a variant in NR5A1. Pelvic magnetic resonance imaging showed absence of uterus and ovaries. The abdominopelvic ultrasound revealed bilateral testicle in bilateral groin. Pathology confirmed testes dysgenesis. Interventions: The patient underwent bilateral orchiectomy at age 12 years and was given a feminizing hormonal treatment of 0.5 mg/day of estradiol valerate tablets. Outcomes: The patient recovered well after surgery and hormonal treatment and had a regression in hirsutism and clitoromegaly. Lessons: 46,XY DSD is a rare disease that the development of chromosomal, gonadal, or anatomical sex is discordant, when diagnosed 46,XY DSD, the identification of an NR5A1 variant should be considered.
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Minh Duc, Bui, Luong Thi Lan Anh, Nong Van Hai e Nguyen Thuy Duong. "Association study of NR5A1 rs1110061 with infertile male in 401 Vietnamese individuals". Vietnam Journal of Biotechnology 19, n. 4 (3 maggio 2022): 625–31. http://dx.doi.org/10.15625/1811-4989/16358.
Abstract (sommario):
Male infertility is a reproductive issue involving defects in the quantity and quality of sperm. Besides the exogenous elements such as harmful habits, pollution, genetic factors including disorders in a single gene, group of genes, or chromosomes, are the etiology causing infertility in men. NR5A1 is well-known as a candidate gene involved in male infertility, including 46, XY disorders of sex development (DSD), cryptorchidism, micropenis, spermatogenic failure, non-obstructive azoospermia, and oligozoospermia. This study aimed to identify the single nucleotide polymorphism (SNP) associated with male infertility in the NR5A1 gene in a Vietnamese cohort of 202 infertile men and 199 healthy controls. By directly sequencing the coding region of the NR5A1 gene in 56 cases and 21 controls, only one missense mutation c.437G>C (p.Gly146Ala; rs1110061) in exon 4 was found. The variant was detected in 34 patients, of which 27 were heterozygous (GC) and 7 were homozygous (CC). In the control group, 15 individuals carried this mutation, including 10 with heterozygous (GC) and 5 with homozygous (CC). To further investigate the association of the polymorphism NR5A1 rs11100061 with male infertility disease, we performed PCR-RFLP in 202 infertile and 199 healthy men to assess the genotypes and alleles. The results indicated that the distribution of the genotypes of the polymorphism was in accordance with Hardy-Weinberg equilibrium (p-values > 0.05). However, no association was detected between the polymorphism and male infertility (p-values > 0.05).
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Mönig, Isabel, Julia Schneidewind, Trine H. Johannsen, Anders Juul, Ralf Werner, Ralf Lünstedt, Wiebke Birnbaum, Louise Marshall, Lutz Wünsch e Olaf Hiort. "Pubertal development in 46,XY patients with NR5A1 mutations". Endocrine 75, n. 2 (6 ottobre 2021): 601–13. http://dx.doi.org/10.1007/s12020-021-02883-y.
Abstract (sommario):
Abstract Purpose Mutations in the NR5A1 gene, encoding the transcription factor Steroidogenic Factor-1, are associated with a highly variable genital phenotype in patients with 46,XY differences of sex development (DSD). Our objective was to analyse the pubertal development in 46,XY patients with NR5A1 mutations by the evaluation of longitudinal clinical and hormonal data at pubertal age. Methods We retrospectively studied a cohort of 10 46,XY patients with a verified NR5A1 mutation and describe clinical features including the external and internal genitalia, testicular volumes, Tanner stages and serum concentrations of LH, FSH, testosterone, AMH, and inhibin B during pubertal transition. Results Patients who first presented in early infancy due to ambiguous genitalia showed spontaneous virilization at pubertal age accompanied by a significant testosterone production despite the decreased gonadal volume. Patients with apparently female external genitalia at birth presented later in life at pubertal age either with signs of virilization and/or absence of female puberty. Testosterone levels were highly variable in this group. In all patients, gonadotropins were constantly in the upper reference range or elevated. Neither the extent of virilization at birth nor the presence of Müllerian structures reliably correlated with the degree of virilization during puberty. Conclusion Patients with NR5A1 mutations regardless of phenotype at birth may demonstrate considerable virilization at puberty. Therefore, it is important to consider sex assignment carefully and avoid irreversible procedures during infancy.
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Kelly, Victoria R., Bin Xu, Rork Kuick, Ronald J. Koenig e Gary D. Hammer. "Dax1 Up-Regulates Oct4 Expression in Mouse Embryonic Stem Cells via LRH-1 and SRA". Molecular Endocrinology 24, n. 12 (1 dicembre 2010): 2281–91. http://dx.doi.org/10.1210/me.2010-0133.
Abstract (sommario):
Abstract Dax1 (Nr0b1) is an atypical orphan nuclear receptor that has recently been shown to play a role in mouse embryonic stem (mES) cell pluripotency. Here we describe a mechanism by which Dax1 maintains pluripotency. In steroidogenic cells, Dax1 protein interacts with the NR5A nuclear receptor steroidogenic factor 1 (Nr5a1) to inhibit transcription of target genes. In mES cells, liver receptor homolog 1 (LRH-1, Nr5a2), the other NR5A family member, is expressed, and LRH-1 has been shown to interact with Dax1. We demonstrate by coimmunoprecipitation that Dax1 is, indeed, able to form a complex with LRH-1 in mES cells. Because Dax1 was historically characterized as an inhibitor of steroidogenic factor 1-mediated transcriptional activation, we hypothesized that Dax1 would inhibit LRH-1 action in mES cells. Therefore, we examined the effect of Dax1 on the LRH-1-mediated activation of the critical ES cell factor Oct4 (Pou5f1). Chromatin immunoprecipitation localized Dax1 to the Oct4 promoter at the LRH-1 binding site, and luciferase assays together with Dax1 overexpression and knockdown experiments revealed that, rather than repress, Dax1 accentuated LRH-1-mediated activation of the Oct4 gene. Similar to our previously published studies that defined the RNA coactivator steroid receptor RNA activator as the critical mediator of Dax1 coactivation function, Dax1 augmentation of LRH-1-mediated Oct4 activation is dependent upon steroid receptor RNA activator. Finally, utilizing published chromatin immunoprecipitation data of whole-genome binding sites of LRH-1 and Dax1, we show that LRH-1 and Dax1 commonly colocalize at 288 genes (43% of LRH-1 target genes), many of which are involved in mES cell pluripotency. Thus, our results indicate that Dax1 plays an important role in the maintenance of pluripotency in mES cells through interaction with LRH-1 and transcriptional activation of Oct4 and other genes.
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Lin, Lin, Pascal Philibert, Bruno Ferraz-de-Souza, Daniel Kelberman, Tessa Homfray, Assunta Albanese, Veruska Molini et al. "Heterozygous Missense Mutations in Steroidogenic Factor 1 (SF1/Ad4BP, NR5A1) Are Associated with 46,XY Disorders of Sex Development with Normal Adrenal Function". Journal of Clinical Endocrinology & Metabolism 92, n. 3 (1 marzo 2007): 991–99. http://dx.doi.org/10.1210/jc.2006-1672.
Abstract (sommario):
Abstract Context: Steroidogenic factor 1 (SF1/AdBP4/FTZF1, NR5A1) is a nuclear receptor transcription factor that plays a key role in regulating adrenal and gonadal development, steroidogenesis, and reproduction. Targeted deletion of Nr5a1 (Sf1) in the mouse results in adrenal and gonadal agenesis, XY sex-reversal, and persistent Müllerian structures in males. Consistent with the murine phenotype, human mutations in SF1 were described initially in two 46,XY individuals with female external genitalia, Müllerian structures (uterus), and primary adrenal failure. Objective: Given recent case reports of haploinsufficiency of SF1 affecting testicular function in humans, we aimed to identify SF1 mutations in a cohort of individuals with a phenotypic spectrum of 46,XY gonadal dysgenesis/impaired androgenization (now termed 46,XY disorders of sex development) with normal adrenal function. Methods and Patients: The study included mutational analysis of NR5A1 in 30 individuals with 46,XY disorders of sex development, followed by functional studies of SF1 activity. Results: Heterozygous missense mutations in NR5A1 were found in four individuals (four of 30, 13%) with this phenotype. These mutations (V15M, M78I, G91S, L437Q) were shown to impair transcriptional activation through abnormal DNA binding (V15M, M78I, G91S), altered subnuclear localization (V15M, M78I), or disruption of the putative ligand-binding pocket (L437Q). Two mutations appeared to be de novo or germline changes. The other two mutations appeared to be inherited in a sex-limited dominant manner because the mother is heterozygous for the change. Conclusions: These studies demonstrate that SF1 mutations are more frequent than previously suspected causes of impaired fetal and postnatal testicular function in 46,XY individuals.
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Fan, Jinjiang, Enrico Campioli, Andrew Midzak, Martine Culty e Vassilios Papadopoulos. "Conditional steroidogenic cell-targeted deletion of TSPO unveils a crucial role in viability and hormone-dependent steroid formation". Proceedings of the National Academy of Sciences 112, n. 23 (26 maggio 2015): 7261–66. http://dx.doi.org/10.1073/pnas.1502670112.
Abstract (sommario):
Translocator protein (TSPO) is a key member of the mitochondrial cholesterol transport complex in steroidogenic tissues. To assess the function of TSPO, we generated two lines of Cre-mediated Tspo conditional knockout (cKO) mice. First, gonadal somatic cell-targeting Amhr2-Cre mice were crossed with Tspo-floxed mice to obtain F1 Tspo Amhr2 cKO mice (Tspofl/fl;Amhr2-Cre/+). The unexpected Mendelian ratio of 4.4% cKO mice was confirmed by genotyping of 12.5-day-postcoitum (dpc) embryos. As Amhr2-Cre is expressed in gonads at 12.5 dpc, these findings suggest preimplantation selection of embryos. Analysis of expression databases revealed elevated levels of Amhr2 in two- and eight-cell zygotes, suggesting ectopic Tspo silencing before the morula stage and demonstrating elevated embryonic lethality and involvement of TSPO in embryonic development. To circumvent this issue, steroidogenic cell-targeting Nr5a1-Cre mice were crossed with Tspo-floxed mice. The resulting Tspofl/fl;Nr5a1-Cre/+ mice were born at a normal Mendelian ratio. Nr5a1-driven Tspo cKO mice exhibited highly reduced Tspo levels in adrenal cortex and gonads. Treatment of mice with human chorionic gonadotropin (hCG) resulted in increased circulating testosterone levels despite extensive lipid droplet depletion. In contrast, Nr5a1-driven Tspo cKO mice lost their ability to form corticosterone in response to adrenocorticotropic hormone (ACTH). Important for ACTH-dependent steroidogenesis, Mc2r, Stard1, and Cypa11a1 levels were unaffected, whereas Scarb1 levels were increased and accumulation of lipid droplets was observed, indicative of a blockade of cholesterol utilization for steroidogenesis. TSPO expression in the adrenal medulla and increased epinephrine production were also observed. In conclusion, TSPO was found necessary for preimplantation embryo development and ACTH-stimulated steroid biosynthesis.
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Guzmán, Adrian, Camilla H. K. Hughes e Bruce D. Murphy. "Orphan nuclear receptors in angiogenesis and follicular development". Reproduction 162, n. 3 (1 settembre 2021): R35—R54. http://dx.doi.org/10.1530/rep-21-0118.
Abstract (sommario):
Orphan nuclear receptors (ONRs) are a subset of the nuclear receptor family that lacks known endogenous ligands. Among 48 nuclear receptors identified in humans, 25 are classified as ONRs. They function as transcription factors and control the expression of a wide range of genes to regulate metabolism, fertility, immunity, angiogenesis, and many other functions. Angiogenic factors are essential during ovarian follicle development, including follicle growth and ovulation. The correct development of blood vessels contributes to preantral and antral follicular development, selection of the dominant follicle or follicles, follicular atresia, and ovulation. Although progress has been made in understanding the molecular mechanisms that regulate follicular angiogenesis, the role of ONRs as regulators is not clear. Based on their functions in other tissues, the ONRs NR1D1 (REV-ERBβ), NR2C2 (TR4), NR2F2 (COUP-TF-II) and NR3B1, 2, and 3 (ERRα, ERRβ and ERRγ) may modulate angiogenesis during antral follicle development. We hypothesize that this is achieved by effects on the expression and function of VEGFA, ANGPT1, THBS1, and soluble VEGFR1. Further, angiogenesis during ovulation is expected to be influenced by ONRs. NR5A2 (LRH-1), which is required for ovulation, regulates angiogenic genes in the ovary, including VEGFA and the upstream regulator of angiogenesis, PGE2. These angiogenic molecules may also be regulated by NR5A1 (SF-1). Evidence from outside the reproductive tract suggests that NR2F2 and NR4A1(NUR77) promote VEGFC and PGF, respectively, and NR4As (NUR77, NOR1) seem to be necessary for the angiogenic effects of VEGFA and PGE2. Together, the data suggest that ONRs are important regulators of follicular angiogenesis.
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Abisad, Daniela Aguilar, Andrea Montano Ballesteros e Alejandro Diaz. "RF02 | PMON309 Two Siblings with p.Arg92Trp Variant in NR5A1 Presenting with Testicular Disorder of Sexual Differentiation". Journal of the Endocrine Society 6, Supplement_1 (1 novembre 2022): A709—A710. http://dx.doi.org/10.1210/jendso/bvac150.1462.
Abstract (sommario):
Abstract Introduction Disorders of sexual differentiation (DSD) are conditions of abnormal chromosomal development leading to atypical gonadal and anatomic sexual characteristics. We present the case of two siblings with 46, XX testicular DSD due to a mutation in the nuclear receptor subfamily 5 group A member 1 gene (NR5A1). While there is extensive literature about pathogenic variants of this gene, this is the first variant that has been shown to cause DSD in XX individuals, rather than XY. Case presentation This is the case of a sibling pair with male phenotype and history of hypospadias and hypogonadism in the setting of 46, XX karyotype. Sibling A presented with hypospadias at birth and hypergonadotropic hypogonadism in childhood, initially managed with testosterone. Testicular biopsy revealed bilateral germ cell aplasia with degeneration of seminiferous tubules. Sibling B presented at age 8 with precocious puberty. He had a history of hypospadias and cryptorchidism at birth. Gonadotropins and testosterone levels were prepubertal. Testicular biopsy showed only Sertoli cells. Their adrenal gland and thyroid function was normal, their bone age was advanced. FISH was negative for the SRY gene in both cases, no ovaries or mullerian structures found in pelvic imaging. DSD genetic panels were sent, resulting positive for the R92W variant in NR5A1. Neither of them have intellectual disability; however, sibling B has attention deficit and hyperactivity disorder (ADHD) and obsessive compulsive disorder (OCD). Family history is remarkable for two uncles that have been unable to conceive. Their mother had oligomenorrhea and difficulty conceiving, typical presentation of a female carrier of this mutation. Discussion and conclusions The majority of DSD in individuals with a 46, XX karyotype are due to congenital adrenal hyperplasia (CAH) secondary to 21-hydroxylase deficiency, however, mutations in NR5A1 have been among the most frequently identified genetic causes of gonadal development disorders and are associated with a wide phenotypic spectrum. NR5A1 is an essential transcription factor that regulates target genes crucial for normal reproductive physiology and endocrine function, controlling several steps of adrenal and gonadal development. While there is extensive literature about the phenotype caused by variants of NR5A1 in XY individuals, the recurrent heterozygous p.Arg92Trp NR5A1 variant R92W that our patients have, is the only one that has been shown to cause DSD in XX individuals, with variable degrees of testis development. It has previously been described, however, in women with primary ovarian insufficiency (POI). Morevariants of this gene will continue to arise, playing a pivotal role in reproductive endocrinology. Presentation: Saturday, June 11, 2022 1:00 p.m. - 1:05 p.m., Saturday, June 11, 2022 1:00 p.m. - 1:05 p.m., Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.
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Lourenço, Diana, Raja Brauner, Lin Lin, Arantzazu De Perdigo, Georges Weryha, Mihaela Muresan, Radia Boudjenah et al. "Mutations in NR5A1 Associated With Ovarian Insufficiency". Obstetrical & Gynecological Survey 64, n. 10 (ottobre 2009): 665–66. http://dx.doi.org/10.1097/01.ogx.0000359268.91477.36.
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de Oliveira, Felipe Rodrigues, Taís Nitsch Mazzola, Maricilda Palandi de Mello, Ana Paula Francese-Santos, Sofia Helena V. de Lemos-Marini, Andrea Trevas Maciel-Guerra, Olaf Hiort, Ralf Werner, Gil Guerra-Junior e Helena Fabbri-Scallet. "DHX37 and NR5A1 Variants Identified in Patients with 46,XY Partial Gonadal Dysgenesis". Life 13, n. 5 (27 aprile 2023): 1093. http://dx.doi.org/10.3390/life13051093.
Abstract (sommario):
The group of disorders known as 46,XY gonadal dysgenesis (GD) is characterized by anomalies in testis determination, including complete and partial GD (PGD) and testicular regression syndrome (TRS). Several genes are known to be involved in sex development pathways, however approximately 50% of all cases remain elusive. Recent studies have identified variants in DHX37, a gene encoding a putative RNA helicase essential in ribosome biogenesis and previously associated with neurodevelopmental disorders, as a cause of PGD and TRS. To investigate the potential role of DHX37 in disorders of sexual development (DSD), 25 individuals with 46,XY DSD were analyzed and putative pathogenic variants were found in four of them. WES analyses were performed on these patients. In DHX37, the variant p.(Arg308Gln), recurrent associated with DSD, was identified in one patient; the p.(Leu467Val), predicted to be deleterious, was found together with an NR5A1 loss-of-function variant in patient 2; and, the p.(Val999Met) was identified in two unrelated patients, one of whom (patient 3) also carried a pathogenic NR5A1 variant. For both patients carrying DHX37 and NR5A1 pathogenic variants, a digenic inheritance is suggested. Our findings support the importance of DHX37 variants as a cause of disorders of sex development, implying a role in testis development.
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Mello, Maricilda Palandi de, Emerson Salvador de Souza França, Helena Campos Fabbri, Andréa Trevas Maciel-Guerra e Gil Guerra-Júnior. "Multifunctional role of steroidogenic factor 1 and disorders of sex development". Arquivos Brasileiros de Endocrinologia & Metabologia 55, n. 8 (novembre 2011): 607–12. http://dx.doi.org/10.1590/s0004-27302011000800015.
Abstract (sommario):
Disorders of sex development (DSD) involve several conditions that result from abnormalities during gonadal determination and differentiation. Some of these disorders may manifest at birth by ambiguous genitalia; others are diagnosed only at puberty, by the delayed onset of secondary sexual characteristics. Sex determination and differentiation in humans are processes that involve the interaction of several genes such as WT1, NR5A1, NR0B1, SOX9, among others, in the testicular pathway, and WNT4, DAX1, FOXL2 and RSPO1, in the ovarian pathway. One of the major proteins in mammalian gonadal differentiation is the steroidogenic nuclear receptor factor 1 (SF1). This review will cover some of the most recent data on SF1 functional roles and findings related to mutations in its coding gene, NR5A1.
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Kalinchenko, Natalia Yur'evna, Tatiana Aleksandrovna Anosova, Vitaliy Alekseevich Ioutsi e Anatoly Nikolaevich Tiulpakov. "The first clinical presentation of disorders of sex development 46 XY due to mutation in Steroidogenic factor 1 (SF1) in Russian Literature". Problems of Endocrinology 62, n. 1 (13 gennaio 2016): 55–59. http://dx.doi.org/10.14341/probl201662155-59.
Abstract (sommario):
Steroidogenic factor 1 (SF1/AdBP4/FTZF1, NR5A1) is a nuclear receptor transcription factor that plays a critical role in different processes of sex development. Homozygous mutations in SF1 result in adrenal failure and complete testicular disgenesis in 46,XY individuals. According to recent studies heterozygous mutations in SF1 are associated with milder phenotype: they are found in children with 46,XY disorders of sex development (DSD) but with apparently normal adrenal structure and function. Here we present for the first time in Russian literature a case of SF1 deficiency. Molecular genetic analysis of NR5A1 gene revealed a novel heterozygous mutation c.951delC p.H317QfsX17. This clinical case demonstrates the importance of molecular genetic studies in DSD 46,XY, especially severe forms.
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Morales-Miranda, A., F. Vilchis, B. Chávez, C. Chan, G. Robles-Díaz e V. Díaz-Sánchez. "EXPRESSION OF NR5A1/SF-1, NR5A2/SF-2, CYP11A1 (P450SCC) AND STAR PROTEIN IN NORMAL HUMAN PANCREAS." Pancreas 29, n. 4 (novembre 2004): 346. http://dx.doi.org/10.1097/00006676-200411000-00085.
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Kalinchenko, Natalia Yu, Anna A. Kolodkina, Nadezda Y. Raygorodskaya e Anatoly N. Tiulpakov. "Clinical and molecular characteristics of patients with 46,XY DSD due to NR5A1 gene mutations". Problems of Endocrinology 66, n. 3 (16 settembre 2020): 62–69. http://dx.doi.org/10.14341/probl12445.
Abstract (sommario):
Steroidogenic factor 1 (SF1, NR5A1) is a nuclear receptor that regulates multiple genes involved in adrenal and gonadal development, steroidogenesis, and the reproductive axis. Human mutations in SF1 were initially found in patients with severe gonadal dysgenesis and primary adrenal failure. However, more recent case reports have suggested that heterozygous mutations in SF1 may also be found in patients with 46,XY partial gonadal dysgenesis and underandrogenization but normal adrenal function. We have analyzed the gene encoding SF1 (NR5A1) in a cohort of 310 Russian patients with 46,XY disorders of sex development (DSD). Heterozygous SF1 variants were found in 36 out of 310 (11.6%) of cases, among them 15 were not previously described. We have not found any phenotype-genotype correlations and any clinical and laboratory markers that would allow to suspect this type of before conducting molecular genetic analysis.
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Zheng, Weiming, Jingying Yang, Qiaorong Jiang, Zhibin He e Lisa M. Halvorson. "Liver receptor homologue-1 regulates gonadotrope function". Journal of Molecular Endocrinology 38, n. 2 (febbraio 2007): 207–19. http://dx.doi.org/10.1677/jme-06-0001.
Abstract (sommario):
Over the past decade, substantial advances have been made in our understanding of the transcription factors which regulate gene expression in gonadotropes. One of the most important of these factors, steroidogenic factor-1 (SF-1; NR5A1) is critical for gonadotropin and GnRH-receptor expression. Interestingly, a closely related nuclear hormone receptor, liver receptor homologue-1 (LRH-1; NR5A2) has recently been detected in the anterior pituitary gland; however, its functional significance in this tissue has not been investigated. For the experiments reported here, we hypothesized that LRH-1 plays a previously unrecognized role in gonadotrope physiology. Towards this end, we first demonstrate LRH-1 mRNA and protein expression in both primary pituitary cells and gonadotrope-derived cell lines. We next show that LRH-1 stimulates promoter activity of the GnRH-receptor and gonadotropin subunit genes. Within the LHβ gene, this response appears to be mediated by DNA-binding and transactivation through previously characterized SF-1 cis-elements. To our knowledge, this is the first report demonstrating a functional role for LRH-1 in the gonadotrope population of the anterior pituitary gland.
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Shi, Boyang, Huijie Lu, Lihong Zhang e Weimin Zhang. "A homologue of Nr5a1 activates cyp19a1a transcription additively with Nr5a2 in ovarian follicular cells of the orange-spotted grouper". Molecular and Cellular Endocrinology 460 (gennaio 2018): 85–93. http://dx.doi.org/10.1016/j.mce.2017.07.008.
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Ferraz-de-Souza, Bruno, Lin Lin e John C. Achermann. "Steroidogenic factor-1 (SF-1, NR5A1) and human disease". Molecular and Cellular Endocrinology 336, n. 1-2 (aprile 2011): 198–205. http://dx.doi.org/10.1016/j.mce.2010.11.006.
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Werner, Ralf, Isabel Mönig, Ralf Lünstedt, Lutz Wünsch, Christoph Thorns, Benedikt Reiz, Alexandra Krause et al. "New NR5A1 mutations and phenotypic variations of gonadal dysgenesis". PLOS ONE 12, n. 5 (1 maggio 2017): e0176720. http://dx.doi.org/10.1371/journal.pone.0176720.
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Zhu, Zhengya, Zhongyuan He, Tao Tang, Fuan Wang, Hongkun Chen, Baoliang Li, Guoliang Chen et al. "Integrative Bioinformatics Analysis Revealed Mitochondrial Dysfunction-Related Genes Underlying Intervertebral Disc Degeneration". Oxidative Medicine and Cellular Longevity 2022 (11 ottobre 2022): 1–35. http://dx.doi.org/10.1155/2022/1372483.
Abstract (sommario):
Objective. Mitochondrial dysfunction plays an important role in intervertebral disc degeneration (IDD). We aim to explore the pathways and key genes that cause mitochondrial dysfunction during IDD and to further reveal the pathogenesis of IDD based on bioinformatic analyses. Methods. Datasets GSE70362 and GSE124272 were downloaded from the Gene Expression Omnibus. Differentially expressed genes (DEGs) of mitochondrial dysfunction between IDD patients and healthy controls were screened by package limma package. Critical genes were identified by adopting gene ontology (GO), Kyoto encyclopedia of genes and genomes (KEGG) pathways, and protein-protein interaction (PPI) networks. We collected both degenerated and normal disc tissues obtained surgically, and we performed western blot and qPCR to verify the key DEGs identified in intervertebral disc tissues. Results. In total, 40 cases of IDD and 24 healthy controls were included. We identified 152 DEGs, including 67 upregulated genes and 85 downregulated genes. Four genes related to mitochondrial dysfunction (SOX9, FLVCR1, NR5A1 and UCHL1) were screened out. Of them, SOX9, FLVCR1, and UCHL1 were down-regulated in peripheral blood and intervertebral disc tissues of IDD patients, while NR5A1 was up-regulated. The analysis of immune infiltration showed the concentrations of mast cells activated were significantly the highest in IDD patients. Compared with the control group, the level of T cells CD4 memory resting was the lowest in the patients. In addition, 24 cases of IDD tissues and 12 cases of normal disc tissues were obtained to verify the results of bioinformatics analysis. Both western blot and qPCR results were consistent with the results of bioinformatics analysis. Conclusion. We identified four genes (SOX9, FLVCR1, NR5A1 and UCHL1) associated with mitochondrial dysfunction that play an important role in the progress of disc degeneration. The identification of these differential genes may provide new insights for the diagnosis and treatment of IDD.
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Lalli, Enzo. "Adrenocortical development and cancer: focus on SF-1". Journal of Molecular Endocrinology 44, n. 6 (3 marzo 2010): 301–7. http://dx.doi.org/10.1677/jme-09-0143.
Abstract (sommario):
Steroidogenic factor-1 (SF-1/Ad4-binding protein; NR5A1) is an essential regulator of tissue-specific gene expression in steroidogenic cells and of adrenogonadal development. Here, I discuss recent data in the literature showing the implication of SF-1 and the importance of its dosage not only during development but also for adrenal cortex tumorigenesis in humans and mice.
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Hu, S. C., J. Ye, A. K. Fathi, X. Fu, S. Huang, Q. Ning e X. P. Luo. "Mutations in NR5A1 and PIN1 associated with idiopathic hypogonadotropic hypogonadism". Genetics and Molecular Research 11, n. 4 (2012): 4575–84. http://dx.doi.org/10.4238/2012.october.9.6.
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Bashamboo, A., e K. McElreavey. "NR5A1/SF-1 and development and function of the ovary". Annales d'Endocrinologie 71, n. 3 (maggio 2010): 177–82. http://dx.doi.org/10.1016/j.ando.2010.02.013.
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Métivier, Raphaël, Yves Le Dréan, Gilles Salbert e Farzad Pakdel. "Interplay between liganded and orphan nuclear receptors controls reproductive pathways". Biochemistry and Cell Biology 78, n. 3 (2 aprile 2000): 345–58. http://dx.doi.org/10.1139/o00-057.
Abstract (sommario):
Nuclear receptors are transcription factors that belong to an evolutionary ancient superfamily. These proteins, which are even present in primitive metazoans, are implicated in all levels of cell fate: proliferation, differentiation, and apoptosis. Some of these nuclear receptors behave as ligand-inducible transcription factors, as they have acquired during evolution the ability to bind ligands. This is the case for some proteins that recognize small hydrophobic signaling molecules, and particularly the estrogen receptor (ER or NR3A1), which regulates the target gene's transcription rate under estrogen binding. It is now known that the ER alone regulates the transcription of many genes, such as those implicated in reproductive functions. However, this ER-mediated signaling pathway could be modulated by other transcription factors. Our work has established that two other orphan nuclear receptors (SF-1 or NR5A1 and the COUP-TFs, NR2F1 and NR2F2) can enhance two ER-regulated genes implicated in salmonid reproductive functions: the ER gene itself, and the sGTHIIβ gene. Moreover, some xenoestrogens could disturb these regulations. Therefore, our data contribute to the concept that interplay between nuclear receptors is an important event for the transcriptional regulation of genes controlling cellular functions.Key words: reproduction, estrogen receptor, SF-1, COUP-TFI, gene transcription, xenobiotics.
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Whitby, Richard J., Jozef Stec, Raymond D. Blind, Sally Dixon, Lisa M. Leesnitzer, Lisa A. Orband-Miller, Shawn P. Williams et al. "Small Molecule Agonists of the Orphan Nuclear Receptors Steroidogenic Factor-1 (SF-1, NR5A1) and Liver Receptor Homologue-1 (LRH-1, NR5A2)". Journal of Medicinal Chemistry 54, n. 7 (14 aprile 2011): 2266–81. http://dx.doi.org/10.1021/jm1014296.
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Zhang, Lingling, Lijun Ding, Yifan Li, Fangxi Zhang, Yanhong Xu, Hongjie Pan, Xiaofeng Wan, Guijun Yan, Fei Yu e Runsheng Li. "EHD3 positively regulated by NR5A1 participates in testosterone synthesis via endocytosis". Life Sciences 278 (agosto 2021): 119570. http://dx.doi.org/10.1016/j.lfs.2021.119570.
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Wang, Chiung-Min, Runhua Liu, Lizhong Wang e Wei-Hsiung Yang. "Acidic Residue Glu199 Increases SUMOylation Level of Nuclear Hormone Receptor NR5A1". International Journal of Molecular Sciences 14, n. 11 (13 novembre 2013): 22331–45. http://dx.doi.org/10.3390/ijms141122331.