Alternative titles; symbols
HGNC Approved Gene Symbol: ESR2
Cytogenetic location: 14q23.2-q23.3 Genomic coordinates (GRCh38): 14:64,226,707-64,338,613 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 14q23.2-q23.3 | ?Ovarian dysgenesis 8 | 618187 | Autosomal dominant | 3 |
Estrogen receptor-beta (ESR2) is a member of the superfamily of nuclear receptors, which can transduce extracellular signals into transcriptional responses.
Mosselman et al. (1996) identified and characterized a human estrogen receptor, which they called estrogen receptor-beta. ESR-beta is homologous to the previously identified ESR-alpha (ESR1; 133430) and has an overlapping but nonidentical tissue distribution. The DNA-binding domain of ESR-beta is 96% conserved compared to ESR, and the ligand-binding domain shows 58% conserved residues. Northern blot analysis showed that ESR-beta is expressed in human thymus, spleen, ovary, and testis.
Kuiper et al. (1996) identified ESR-beta from a rat prostate cDNA library. Rat ESR-beta is expressed in rat prostate and ovary and is homologous to rat ESR (95% conserved DNA-binding domain; 55% conserved ligand-binding domain).
By screening for ESRB clones in a testis cDNA library, Moore et al. (1998) obtained 3 splice variants of ESRB, which they called ER-beta-1, -beta-2, and -beta-3. The deduced proteins contain 530, 495, and 513 amino acids, respectively. These isoforms were considered full-length because each contains an identical N-terminal domain, a central DNA-binding domain, and a C-terminal ligand-binding domain. They differ from each other following residue 469 in helix 10 of the ligand-binding domain. By PCR of testis and breast cancer cell line cDNA libraries, Moore et al. (1998) cloned 2 further variants, ER-beta-4 and ER-beta-5, which encode only a portion of the C-terminal ligand-binding domain of full-length ER-beta, followed by unique sequences. PCR analysis revealed variable expression of all isoforms except ER-beta-3 in a wide range of normal tissues. ER-beta-1 was highly expressed in testis and ovary; ER-beta-2 was highly expressed in spleen, thymus, testis, and ovary; ER-beta-4 was highly expressed in testis; and ER-beta-5 was highly expressed in placenta, spleen, and leukocytes. Lower levels of these variants were detected in several tissues.
By immunohistochemical analysis of ESRB in an 8-week-old male embryo, Baetens et al. (2018) observed expression in the developing eye, particularly in the corneal epithelium and endothelium, primitive lens neurons, primitive retinal cells, and retinal pigment epithelium. Expression was also seen in the mucosa of the developing intestine, and in the developing brain, specifically the primitive neurons of the germinal matrix. No ESRB staining was present in the developing testis.
Enmark et al. (1997) reported the genomic structure of the ESR2 gene, which they referred to as ER-beta. The ESR2 gene comprises 8 exons spanning approximately 40 kb. ESR2 is expressed in multiple tissues, including developing spermatids of the testis and in ovarian granulosa cells. Enmark et al. (1997) concluded that this finding may be pertinent to the investigation of the effects of environmental estrogens on sperm counts and the participation of estrogens in the regulation of follicular growth in humans.
Mosselman et al. (1996) assigned the ESR2 gene to 14q by study of somatic cell hybrids. Tsukamoto et al. (1998) used a CA repeat at the ESR2 locus to confirm mapping to 14q by linkage to a marker in a radiation hybrid mapping panel. Using PCR and FISH, Enmark et al. (1997) mapped the ESR2 gene to 14q22-q24.
Mosselman et al. (1996) showed ESR-beta to be transactivated by 17-beta-estradiol (E2), and ICI-164384 to be a potent antagonist for ESR-beta.
ESR2 has high homology to ESR1 in the DNA- and ligand-binding domains, but encodes a distinct transcriptional activating function-1 (AF-1) domain. Using RT-PCR analysis of total RNA from 38 human pituitary adenomas, Chaidarun et al. (1998) found that ESR2 mRNA was coexpressed with ESR1 and its splice variants in 60% of prolactinomas, 100% of mixed growth hormone (GH; 139250)/prolactin (PRL; 176760) tumors, and 29% of gonadotroph tumors. ESR2 gene expression was not limited to ESR1-positive tumor subtypes, however, and was also found in 100% of null cell tumors, 80% of somatotroph tumors, and 60% of corticotroph tumors. Because ESR2 is coexpressed with ESR1 and its splice variants in prolactinomas and gonadotroph tumors, Chaidarun et al. (1998) characterized the potential interactions between ESR2 and ESR1. The findings suggested that ESR2 has a minor role in mediating E2 responses in ESR1-positive tumors, but may be the main mediator of E2-stimulated gene expression when expressed alone in somatotroph, corticotroph, and null cell tumors. Therefore, E2-mediated gene expression in normal and neoplastic pituitary appears to be highly dependent on the expression of ESR1 and ESR2 isoforms, which have varying transcriptional activities. Moore et al. (1998) described 5 isoforms of human ER-beta, designated ER-beta-1 through ER-beta-5, which differ in their C-terminal sequences and tissue expression patterns.
The 2 isoforms of human ESR, ESR-alpha and ESR-beta, occur with distinct tissue and cell patterns of expression. Additional ESR isoforms, generated by alternative mRNA splicing, have been defined in several tissues and are postulated to play a role in tumorigenesis or in modulating the estrogen response. By RT-PCR and hybridization blotting analysis, Shupnik et al. (1998) examined 71 human pituitary adenomas of varying phenotypes and 6 normal pituitary specimens for ESR mRNA isoforms. All 14 prolactinomas contained ESRA, and 5 of 14 contained ESRB mRNA. In comparison, 6 tumors that expressed PRL and GH expressed ESRB (4 of 6) more frequently than ESRA (3 of 6). ESRB mRNA was also found more frequently in null cell (8 of 24 ESRA and 14 of 24 ESRB) and gonadotrope (13 of 21 ESRA and 18 of 21 ESRB) tumors. Additionally, ESRB was found in 4 of 6 tumors that contained only GH, although ESRA was not observed in this tumor type. Expression of the 2 ESR isoforms within a tumor type was overlapping, but some tumors contained only 1 isoform. A novel ESRB mRNA splice variant, missing exon 2, was observed in a majority of all ESRB-positive tumors. The authors concluded that expression of the ESR isoforms, as well as of the mRNA splice variants, may influence the biologic properties of these tumors and affect their ability to respond to estrogen and antiestrogen therapies.
Using in vitro band shift assays, Moore et al. (1998) showed that all full-length ER-beta isoforms bound DNA containing a canonical ERE motif, and that they formed DNA-binding homodimers and heterodimers with each other and with ER-alpha.
Speirs et al. (2000) examined mRNA expression of ESRA, wildtype ESRB (mRNA and protein), and ESRB exon 5 deletion variants (ESRB-delta5) in samples of normal human mammary gland obtained from 37 premenopausal subjects undergoing reduction mammoplasty. Comparing individual expression, ESRB mRNA predominated, expressed in 34 of 37 samples (91%), whereas ESRA was found in 21 of 37 cases (57%). Most samples either coexpressed ESRA with ESRB (54%) or expressed just ESRB (38%). Immunohistochemical analysis revealed that ESRB mRNA expression mirrored that of protein. Expression of wildtype and ESRB-delta5 was analyzed, and their association with ESRA was compared. Most samples coexpressed wildtype ESRB and the splice variant (62%; P = 0.05), with 30% exclusively expressing wildtype ESRB. Although samples coexpressing wildtype and variant ESRB showed no statistical association with ESRA, those samples expressing only wildtype ESRB showed a trend toward associations with ESRA (P = 0.07). The authors concluded that their data support a role for ESRB in the normal human mammary gland, where they proposed it may be the dominant receptor.
Chu et al. (2000) studied the patterns of both ESRA and ESRB gene expression in a panel of ovarian tumors consisting of granulosa cell tumors (GCT) and serous and mucinous cystadenocarcinomas as well as in normal ovary. Expression was determined by RT-PCR using gene- and isoform-specific primers and probes combined with Southern blot analysis of the PCR products. Widespread expression of ESRA was observed in all tumor types, but at relatively low levels. ESRB is expressed predominantly in GCT, with lower levels in mucinous tumors and very low levels in serous tumors. The ESRB2 splice variant reported in rodents (Petersen et al., 1998) was not observed. Only very low levels of the exon 5, exon 6, and exon 5/6 deletion variants were detected. The C-terminal truncation variant ESRB(cx), however, exhibited widespread expression across all the tumor types. The authors concluded that as ESRB(cx) is a ligand-independent antagonist of ESR-alpha (ESRA; 133430) action (Ogawa et al., 1998), the relative ratios of ESRB(cx), ESRA, and ESRB may influence the response of a tumor to antiestrogen therapy.
Osterlund et al. (2000) investigated the anatomic distribution pattern of ESRB mRNA expression in the human forebrain. Overall, the ESRB mRNA hybridization signal was relatively low, but the most abundant ESRB mRNA areas were the hippocampal formation (primarily the subiculum), claustrum, and cerebral cortex; expression was also present in the subthalamic nucleus and thalamus (ventral lateral nucleus). In contrast to ESRA (studied on adjacent brain sections), ESRB mRNA expression was low in the hypothalamus and amygdala. Based on the observed anatomic distribution of the human ESRB gene expression, the authors suggested a putative role for ESRB in the modulation of cognition, memory, and motor functions.
Chiang et al. (2000) examined the regulation of ESRA and ESRB expression by human chorionic gonadotropin (CG; see 118850) in human granulosa-luteal cells (GLCs). CG treatment (10 IU/mL) significantly attenuated the ESRA (45%) and ESRB (40%) mRNA levels. The CG-induced decrease in ESRA and ESRB expression was mimicked by 8-bromo-cAMP and forskolin treatment. Next, the effect of gonadotropin-releasing hormone (GNRH; 152760) on estrogen receptor expression was studied. Sixty-eight percent and 60% decreases in ESRA and ESRB mRNA levels, respectively, were observed after treatment with 0.1 micromol/L GNRH agonist (GNRHa). Pretreatment of the cells with a protein kinase C (PKC; see 176960) inhibitor completely reversed the GNRHa-induced downregulation of ESRA and ESRB expression, suggesting the involvement of PKC in GNRH signal transduction in GLCs. Chiang et al. (2000) observed a differential expression of ESRA and ESRB mRNA in GLCs in vitro. The authors concluded that the demonstration of CG- and GNRHa-induced downregulation of ESRA and ESRB gene expression suggests that CG and GNRH may contribute to the control of granulosa-luteal cell function. Furthermore, they inferred that the effects of CG and GNRH on ESRA and ESRB expression in GLCs are mediated in part by activation of PKA (see 176911) and PKC signaling pathways, respectively.
The paraventricular nucleus (PVN) and the supraoptic nucleus (SON) in the rat contain estrogen-regulated oxytocin (OXT; 167050) and arginine-vasopressin (AVP; 192340) systems, but little or no estrogen receptor-alpha. Using estradiol-treated ovariectomized young adult Sprague-Dawley rats and dual-labeled immunocytochemistry, Alves et al. (1998) showed that OXT-ir (OXT-immunoreactivity) colocalized with ESR-beta-ir in the parvicellular subnuclei of PVN, but that there was little AVP-/ESR-beta-ir. In contrast, in the SON, most nuclear ESR-beta-ir colocalized with AVP-ir, whereas few OXT-/ESR-beta-ir dual-labeled cells were observed. These results suggested that estrogen can directly modulate specific OXT and AVP systems through an ESR-beta-mediated mechanism, in a tissue specific manner.
Esmaeli et al. (2000) found immunohistochemical evidence that estrogen receptors are present in the meibomian glands of the upper eyelid. Unlike sebaceous glands elsewhere on the skin, the meibomian glands lack androgen receptors. Esmaeli et al. (2000) suggested that these eyelid estrogen receptors may play a role in modulation of the tear film lipid layer. They concluded that estrogen receptor activity may be linked to meibomian gland dysfunction and dry eye syndrome.
Pelletier and El-Alfy (2000) studied the immunocytochemical localization of ESRA (133430) and ESRB in human reproductive tissues. In the ovary, ESRB immunoreactivity was found in nuclei of granulosa cells of growing follicles at all stages from primary to mature follicles, interstitial gland, and germinal epithelium cells. Nuclear staining for ESRA occurred in thecal, interstitial gland, and germinal epithelium cells. In the uterus, strong ESRA immunoreactivity was detected in nuclei of epithelial, stromal, and muscle cells. Similar localization was obtained for ESRB, although the staining was much weaker. In the vagina, only ESRA could be detected; a nuclear reaction was observed in deep layers of the stratified epithelium as well as in stromal and muscle cells. In the mammary gland, both ESR subtypes were observed in epithelial and stromal cells. In the testis, ESRB was detected in the nuclei of Sertoli and Leydig cells, whereas ESRA immunoreactivity was only observed in Leydig cells, with no tubular labeling. In the efferent ducts, only ESRB could be detected, whereas neither ESRB nor ESRA could be found in the epididymis. In the prostate, ESRB nuclear immunolabeling was observed in both basal and secretory cells in alveoli as well as in stromal cells, whereas ESRA could not be detected. The authors concluded that there is a cell-specific localization for each of the ESR subtypes in the majority of the reproductive organs studied.
Saunders et al. (2002) examined the expression of wildtype (ER-beta-1) and variant (ER-beta-2) ESR2 receptors in human testes. Immunoexpression of ER-beta-1 was most intense in pachytene spermatocytes and round spermatids, whereas low levels of expression were detected in Sertoli cells, spermatogonia, preleptotene, leptotene, zygotene, and diplotene spermatocytes. Highest levels of expression of ER-beta-2 protein were detected in Sertoli cells and spermatogonia with low/variable expression in preleptotene, pachytene, and diplotene spermatocytes. No immunostaining was detected in elongating spermatids. Most interstitial cells expressed more ER-beta-2 than ER-beta-1. The authors speculated that the cells most susceptible to modulation by estrogenic ligands are round spermatids in which levels of expression of ER-beta-1 are high. In contrast, expression of ER-beta-2, an isoform that may act as a dominant-negative inhibitor of estrogen receptor action in Sertoli cells and spermatogonia, could protect these cells from adverse effects of estrogens.
Bord et al. (2001) established the cellular distribution of ESRA and ESRB in neonatal human rib bone. ESRA and ESRB immunoreactivity was seen in proliferative and prehypertrophic chondrocytes in the growth plate, with lower levels of expression in the late hypertrophic zone. Different patterns of expression of the 2 ESRs were seen in bone. In cortical bone, intense staining for ESRA was observed in osteoblasts and osteocytes adjacent to the periosteal-forming surface and in osteoclasts on the opposing resorbing surface. In cancellous bone, ESRB was strongly expressed in both osteoblasts and osteocytes, whereas only low expression of ESRA was seen in these areas. Nuclear and cytoplasmic staining for ESRB was apparent in osteoclasts. The authors concluded that these observations demonstrate distinct patterns of expression for the 2 ESR subtypes in developing human bone and indicate functions in both the growth plate and mineralized bone. In the latter, ESRA is predominantly expressed in cortical bone, whereas ESRB shows higher levels of expression in cancellous bone.
Aguirre et al. (2007) demonstrated that extracellular signal-regulated kinases (see ERKs, 176948) are not activated by stretching in osteocytic and osteoblastic cells in which both ESR1 and ESR2 have been knocked out or knocked down; this effect was partially reversed by transfection of either of the 2 human ESRs, and fully by transfection of both receptors. ERK activation in response to stretching was also recovered by transfecting the ligand-binding domain of either receptor or an ESR1 mutant that does not bind estrogens. Mechanoresponsiveness was restored by transfecting ESR1 targeted to the plasma membrane but not to the nucleus, and ESR1 mutants with impaired plasma membrane localization or binding to caveolin-1 (601047) failed to confer ERK activation in response to stretching. An ESR antagonist abrogated ERK activation as well as the antiapoptotic effect of mechanical stimulation. Aguirre et al. (2007) concluded that in addition to their role as ligand-dependent mediators of the effects of estrogens, the ESRs participate in the transduction of mechanical forces into prosurvival signaling in bone cells in a ligand-independent manner.
Pasquali et al. (2001) investigated the expression of ESRA and ESRB in normal and malignant primary cultures of human prostate epithelial cells and prostate fibroblasts and in the prostate tissue donors. Both ESRA and ESRB mRNAs were found by RT-PCR analysis in 6 normal prostate epithelial cell cultures and normal prostate tissues and in only 1 of 6 cancerous prostate epithelial cell cultures and in the respective cancer tissue donor. The other 5 cancerous epithelial cultures and related cancer tissue donors and all normal and cancerous fibroblast cultures expressed ESRA mRNA alone. Immunoblot analysis, using a polyclonal anti-ESRB (C-terminal) antibody, demonstrated ESRB protein in lysates of all normal epithelial and in 1 of the 6 cancerous epithelial cultures. The authors concluded that the ESRB gene is expressed together with ESRA in normal prostates and prostate epithelial cells, whereas it is barely detectable in prostate cancer and cancerous prostate epithelial cells. They also conclude that prostate malignancy is associated with a potential disorder of estrogen receptor-mediated pathways.
The therapeutic effectiveness of selective estrogen receptor modulators such as tamoxifen and raloxifene in breast cancer depends on their antiestrogenic activity. In the uterus, however, tamoxifen is estrogenic. Shang and Brown (2002) showed that both tamoxifen and raloxifene induce the recruitment of corepressors to target gene promoters in mammary cells. In endometrial cells, tamoxifen, but not raloxifene, acts like estrogen by stimulating the recruitment of coactivators to a subset of genes. The estrogen-like activity of tamoxifen in the uterus requires a high level of steroid receptor coactivator-1 (SRC1; 602691) expression. Thus, Shang and Brown (2002) concluded that cell type- and promoter-specific differences in coregulator recruitment determine the cellular response to selective estrogen receptor modulators.
Auboeuf et al. (2002) examined the impact of transcription mediated by steroid receptors, including progesterone and estrogen receptors, on RNA processing using reporter genes subject to alternative splicing driven by steroid-sensitive promoters. Steroid hormones affected the processing of pre-mRNA synthesized from steroid-sensitive promoters, but not from steroid unresponsive promoters, in a steroid receptor-dependent and receptor-selective manner. Several nuclear receptor coregulators showed differential splicing effects, suggesting that steroid hormone receptors may simultaneously control gene transcription activity and exon content of the product mRNA by recruiting coregulators involved in both processes.
A heterodimer of the dioxin receptor (AHR; 600253) and ARNT (126110), which are basic helix-loop-helix/PAS family transcription factors, mediates most of the toxic effects of dioxins. Ohtake et al. (2003) demonstrated that the agonist-activated AHR/ARNT heterodimer directly associates with the estrogen receptors ER-alpha (133430) and ER-beta. They showed that this association results in the recruitment of unliganded estrogen receptor and the coactivator p300 (602700) to estrogen-responsive gene promoters, leading to activation of transcription and estrogenic effects. The function of liganded estrogen receptor was found to be attenuated. Estrogenic actions of AHR agonists were detected in wildtype ovariectomized mouse uteri, but were absent in Ahr -/- or Er-alpha -/- ovariectomized mice. Ohtake et al. (2003) concluded that their findings suggest a novel mechanism by which estrogen receptor-mediated estrogen signaling is modulated by a coregulatory-like function of activated AHR/ARNT, giving rise to adverse estrogen-related actions of dioxin-type environmental contaminants.
In immunocytochemistry studies, Yang et al. (2004) found that ER-beta colocalized almost exclusively with a mitochondrial marker in rat primary neuron, primary cardiomyocyte, and a murine hippocampal cell line. The colocalization of ER-beta and mitochondrial markers was identified by both fluorescence and confocal microscopy. No translocation of ER-beta into the nucleus on 17-beta-estradiol treatment was seen using immunocytochemistry. The study demonstrated that ER-beta is localized to mitochondria, suggesting a role for mitochondrial ER-beta in estrogen effects on this important organelle.
Hurtado et al. (2008) showed that estrogen-ER and tamoxifen-ER complexes directly repress ERBB2 (164870) transcription by means of a cis-regulatory element within the ERBB2 gene in human cell lines. They implicated the paired box-2 gene product (PAX2; 167409), in a previously unrecognized role, as a crucial mediator of ER repression of ERBB2 by the anticancer drug tamoxifen. Hurtado et al. (2008) showed that PAX2 and the ER coactivator AIB1/SRC3 (601937) compete for binding and regulation of ERBB2 transcription, the outcome of which determines tamoxifen response in breast cancer cells. The repression of ERBB2 by ER-PAX2 links these 2 breast cancer subtypes and suggests that aggressive ERBB2-positive tumors can originate from ER-positive luminal tumors by circumventing this repressive mechanism. Hurtado et al. (2008) concluded that their data provided mechanistic insight into the molecular basis of endocrine resistance in breast cancer.
Xue et al. (2007) identified a CpG island in the promoter region (-197/+359) of the ESR2 gene, and found that it showed significantly higher methylation in 8 primary endometrial cell samples compared to 8 endometriotic cell samples. Demethylation significantly increased ESR2 mRNA levels in endometrial cells, and the activity of the ESR2 promoter was strongly inactivated by in vitro methylation. The findings indicated that methylation of a CpG island at the ESR2 promoter region may be involved in differential expression of ESR2 in endometriosis and endometrium. These findings may be applied to a number of areas ranging from diagnosis to the treatment of endometriosis (131200).
Wang et al. (2008) found that human HPIP (PBXIP1; 618819) interacted with both ER-alpha and ER-beta in mammalian cells. Overexpression and knockdown analyses revealed that HPIP interaction increased expression of ER-alpha target genes by enhancing phosphorylation of ER-alpha at ser167 by MAPK and AKT. Immunoprecipitation experiments demonstrated that ER-beta also interacted with ER-alpha, thereby decreasing binding of ER-alpha to HPIP and inhibiting expression of ER-alpha target genes.
E2 enhances the activity of the Na+/K+ ion-exchanging ATPase (see 182310) in various tissues and cells. Li et al. (2011) found that NDRG2 (605272) had a role in E2-dependent upregulation of Na+/K+ ATPase in human cell lines. Chromatin immunoprecipitation, EMSA, and mutation analysis showed that E2 upregulated NDRG2 expression via binding of liganded ER-beta, but not ER-alpha, to an estrogen receptor element in the NDRG2 promoter. Immunoprecipitation analysis and inhibitor studies indicated that upregulated NDRG2 stabilized the Na+/K+ ATPase by directly binding to ATPase beta subunit-1 (ATP1B1; 182330), protecting it from ubiquitination and proteasome-mediated degradation. Knockdown of either ESRB2 or NDRG2 attenuated the effects of E2 on Na+/K+ ATPase stability and function.
Ovarian Dysgenesis 8
In a 16.5-year-old 46,XX East African orphan with ovarian dysgenesis (ODG8; 618187), Lang-Muritano et al. (2018) identified heterozygosity for a missense mutation in the ERS2 gene (K314R; 601663.0001) that was not found in controls or the ExAC database. Functional analysis revealed that the K314R mutant is completely inactive, with a dominant-negative effect on wildtype ESR2.
Associations Pending Confirmation
Tsukamoto et al. (1998) identified a polymorphic dinucleotide CA repeat marker from a genomic clone containing the human ESR2 gene. High heterozygosity (0.93) made this polymorphism a useful marker in the genetic study of disorders affecting the female endocrine system, as well as calcium metabolism and cancers of the breast, uterus, and ovary.
Rosenkranz et al. (1998) screened the coding region and part of the 5-prime and 3-prime untranslated regions of the ESR2 gene in 96 extremely obese children and adolescents, 50 patients with anorexia nervosa (606788), 28 patients with bulimia nervosa (607499), and 25 healthy underweight individuals. They detected 5 different sequence variants. The authors concluded that the ESR2 gene harbors several different mutations and polymorphisms, none of which can readily be associated with the above phenotypes.
To elucidate the possible role of genetic variation in the androgen receptor (AR; 313700), ESRA, and ESRB on serum androgen levels in premenopausal women, Westberg et al. (2001) studied the CAG repeat polymorphism of the AR gene, the TA repeat polymorphism of the ESRA gene, and the CA repeat polymorphism of the ESRB gene in a population-based cohort of 270 women. Women with relatively few CAG repeats in the AR gene, resulting in higher transcriptional activity of the receptor, displayed higher levels of serum androgens, but lower levels of LH (see 152780), than women with longer CAG repeat sequences. The CA repeat of the ESRB gene also was associated with androgen and sex steroid hormone-binding globulin (SHBG; 182205) levels; women with relatively short repeat regions hence displayed higher hormone levels and lower SHBG levels than those with many CA repeats. In contrast, the TA repeat of the ESRA gene was not associated with the levels of any of the hormones measured. The authors concluded that serum levels of androgens in premenopausal women may be influenced by variants of the AR gene and the ESRB gene, respectively.
Ogawa et al. (2000) investigated the association between the CA dinucleotide repeat polymorphism within ESR2 and systemic blood pressure in 187 healthy postmenopausal Japanese women. When the subjects were separated into 2 groups, 1 with members having at least 1 allele with 26 CA repeats and the other with members who did not, Ogawa et al. (2000) identified that those in the former group had significantly higher systolic blood pressure than those in the latter (mean +/- standard deviation, 146.0 +/- 25.0 vs 136.6 +/- 23.4; P = 0.032).
Forsell et al. (2001) investigated the CA repeat in intron 5 of the ESRB gene in 336 Alzheimer disease (AD; 104300) patients and in 110 healthy age- and gender-matched controls. There was no significant difference between AD patients and controls when all alleles were compared. However, a significant difference was found when allele 5 (155 bp) was studied, as this allele was seen in 13.6% of the controls but only in 8.0% of the AD patients (p of 0.014). Supporting the hypothesis that allele 5 is implicated in the prevention of AD, no AD patient homozygous for this allele was seen, in contrast to 3 homozygous controls. Forsell et al. (2001) suggested that the intronic association identified could be in linkage disequilibrium with a mutation elsewhere in the ESRB gene.
In a case-control cohort of 158 Greek patients with idiopathic osteoarthritis of the knees (see 165720) and 193 controls, Fytili et al. (2005) studied long (L) and short (S) alleles of the -1174(TA)n, 1092+3607(CA)n, and 172(CAG)n repeat polymorphisms of the ESR1, ESR2, and AR genes, respectively. When odds ratios were adjusted for various risk factors, it was observed that women with LL genotypes for ESR2 and AR genes showed significantly increased risk for the development of osteoarthritis (p = 0.002 and 0.001, respectively).
Beleza-Meireles et al. (2007) studied the effect of several ESR2 gene variants on the risk of hypospadias (see 146450) in a Swedish cohort of 354 boys with nonsyndromic hypospadias and 380 healthy controls. Association was identified with longer variants of the (CA)n polymorphism in intron 6 and with a region of intense transcription factor binding, in the putative promoter region, mapping to rs2987983 and rs10483774. The 2 regions are in low linkage disequilibrium, meaning that they are not necessarily inherited together as a haplotype; logistic regression analysis indicated that these 2 risk effects are not independent.
In a 15-year-old 46,XY girl with absence of pubertal development, facial dysmorphism, and ocular anomalies mapping to chromosome 14, Baetens et al. (2018) sequenced the candidate gene ESR2 and identified homozygosity for a 3-bp deletion (N181del; 601663.0002) for which her unaffected parents and an unaffected 46,XX sister were heterozygous. Targeted resequencing of ESR2 in 73 Belgian and 40 Brazilian 46,XY patients with disorders of sex development (DSD) revealed 2 unrelated patients with nonsyndromic DSD who were heterozygous for missense variants. One was a maternally inherited G84V change at a moderately conserved residue; however, functional evaluation showed activity similar to wildtype. The other was an L426R variant (601663.0003) that showed significantly increased activity compared to wildtype protein and involved a highly conserved residue within the LBD domain; segregation information was unavailable for that family. The N181del variant also showed significantly increased transcriptional activation compared to wildtype ESR2; the proband's heterozygous father appeared as unaffected in the pedigree in the report, but his phenotype was not discussed. Examination of whole-exome sequencing data from the probands excluded the presence of other likely pathogenic variants.
Lubahn et al. (1993) and Korach et al. (1996) described the pleiotropic effects of disruption of the Esr-alpha gene in knockout mice. The findings included absence of breast development in females and infertility caused by reproductive tract and gonadal and behavioral abnormalities in both sexes. Krege et al. (1998) performed comparable studies in knockout mice which demonstrated that mice homozygous for a disruption of the Esr-beta gene exhibited phenotypes distinct from those of the Esr-alpha knockout mice. The Esrb-deficient mice developed normally and were indistinguishable grossly and histologically as young adults from their littermates. RNA analysis and immunocytochemistry showed that the tissues from the Esrb -/- mice lacked normal Esrb RNA and protein. Breeding experiments with young, sexually mature females showed that they are fertile and exhibit normal sexual behavior, but have fewer and smaller litters than wildtype mice. Superovulation experiments indicated that this reduction in fertility is a result of reduced ovarian efficiency. Mutant females had normal breast development and lactated normally. Young, sexually mature male mice showed no overt abnormalities and reproduced normally. Older mutant males displayed signs of prostate and bladder hyperplasia. The results indicated that ESRB is essential for normal ovulation efficiency but is not essential for female or male sexual differentiation, fertility, or lactation.
To clarify the role of estrogen signaling in reproductive tract development and function, Couse et al. (1999) generated mice lacking Esra and Esrb by targeted disruption. Esra/Esrb knockout males were infertile but possessed a grossly normal reproductive tract. They exhibited various stages of spermatogenesis, but the numbers and motility of epididymal sperm were reduced significantly. Esra/Esrb knockout females exhibited proper differentiation of the mullerian-derived structures of the uterus, cervix, and upper vagina, but these structures were severely hypoplastic in adults. Similar uterine hypoplasia was observed in Esra, but not in Esrb, knockout mice. The ovaries of adult Esra/Esrb knockout females exhibited morphologic phenotypes that were clearly distinct from those of the prepubertal Esra/Esrb knockout females and the individual estrogen receptor knockout mice. The double-knockout female ovaries had structures resembling seminiferous tubules of the testis. Within the lumen of the tubule-like structures were degenerating granulosa cells and cells resembling Sertoli cells of the testis. Couse et al. (1999) argued that certain characteristics of the adult Esra/Esrb knockout ovary indicated redifferentiation of varying components rather than a developmental phenomenon: the absence of similar structures in prepubertal Esra/Esrb knockout ovaries; the consistent spherical shape of the tubules, suggesting origination from a once healthy follicle; and age-related increases in the area of transdifferentiation. The ovaries of adult Esra/Esrb knockout females expressed mullerian-inhibiting substance (600957), sulfated glycoprotein-2 (185430), and Sox9 (608160). Couse et al. (1999) concluded that the loss of both receptors leads to an ovarian phenotype that is distinct from that of the individual estrogen receptor knockout mutants, which indicates that both receptors are required for the maintenance of germ and somatic cells in the postnatal ovary.
Because of the poor reproductive capacity of Esrb knockout (BERKO) female mice, as indicated by small litter size and multiple resorbed fetuses, Weihua et al. (2000) studied the role of uterine Esrb. In the immature uterus, Esra and Esrb are expressed at comparable levels in the epithelium and stroma, and 17-beta-estradiol (E2) treatment decreases Esrb in the stroma. Increased cell proliferation and exaggerated response to E2 in BERKO mice suggested that ESRB plays a role in modulation of the effects of ESRA and in addition (or as a consequence of this) has an antiproliferative function in the immature uterus.
Krezel et al. (2001) studied the contribution of estrogen receptors in modulation of emotional processes and analyzed the effects of deleting Esr-alpha or Esr-beta in mice. Behavior consistent with increased anxiety was observed principally in Esrb-mutant females and was associated with a reduced threshold for the induction of synaptic plasticity in the basolateral amygdala. Krezel et al. (2001) suggested that local increase of 5-hydroxytryptamine-1A receptor (109760) expression in medial amygdala may contribute to these changes. Based on their data, they concluded that, particularly in females, there is an important role for ESRB-mediated estrogen signaling in the processing of emotional behavior.
Zhu et al. (2002) showed that vascular smooth muscle cells and blood vessels from Esrb-deficient mice exhibited multiple functional abnormalities. In wildtype mouse blood vessels, estrogen attenuates vasoconstriction by an Esrb-mediated increase in inducible nitric oxide synthase expression. In contrast, estrogen augments vasoconstriction in blood vessels from Esrb-deficient mice. Vascular smooth muscle cells isolated from Esrb-deficient mice showed multiple abnormalities of ion channel function. Furthermore, Zhu et al. (2002) showed that Esrb-deficient mice developed sustained systolic and diastolic hypertension as they aged. Zhu et al. (2002) concluded that their data support an essential role for ESRB in the regulation of vascular function and blood pressure.
Rissman et al. (2002) provided evidence that E2 affects learning and memory via Esr2 in mice. Esr2 knockout and wildtype littermates were tested for spatial learning in the Morris water maze after ovariectomy, appropriate control treatment, or 1 of 2 physiologic doses of E2. Regardless of treatment, all wildtype females displayed significant learning. However, the Esr2 knockouts given the low dose of E2 were delayed in learning acquisition, and the knockouts administered the higher dose of E2 failed to learn the task. These data showed that ESR2 is required for optimal spatial learning and may have implications for hormone replacement therapy in women.
Wang et al. (2001) observed that the brains of adult Esrb -/- mice showed regional neuronal hypocellularity, especially in the cerebral cortex. Using Esrb -/- mice, Wang et al. (2003) showed that Esrb was necessary for late embryonic development of the brain and was involved in both neuronal migration and apoptosis. The findings suggested that, by influencing migration and neuronal survival, ESRB has an important role in brain development.
Fan et al. (2006) found that embryonic Esr2 -/- mice showed lower calretinin (CALB2; 114051) expression than wildtype mice in the hippocampus, thalamus, and amygdala at embryonic days 16.5 and 18.5. Egfr (131550) expression was lower in the cortex of Esr2 -/- mice than wildtype mice at day 15.5 and, unlike wildtype mice, was absent from the superficial marginal zone. Fan et al. (2006) concluded that ESR2 is necessary for the development of calretinin-positive GABAergic interneurons in the embryonic brain and for neuronal migration in the cortex through modulation of EGFR expression at middle and late embryonic stages.
Shim et al. (2003) showed that by 1.5 years of age, Esrb knockout mice developed pronounced splenomegaly that was much more severe in females than in males. Further characterization showed that the absence of Esrb resulted in a myeloproliferative disease resembling human chronic myeloid leukemia with lymphoid blast crisis. The results indicated a previously unknown role for ESRB in regulating the differentiation of pluripotent hematopoietic progenitor cells and suggested that Esrb-null mice could be a model for myeloid and lymphoid leukemia. Furthermore, Shim et al. (2003) suggested that agonists of ESRB might have clinical value in the treatment of leukemia.
Kudwa et al. (2005) studied the effects of Esr2 on male neural sex behavior, which comprises both masculinization, the development of male-type behavior, and defeminization, the reduction of female-type behavior. They found that gonadectomized Esr2-null male mice displayed enhanced receptive lordosis posturing, a female sexual behavior, compared to wildtype gonadectomized male mice. In contrast, there was no difference in male sexual behavior between Esr2-null gonad-intact mice and wildtype gonad-intact mice, as demonstrated by mounting, ejaculation, and sniffing of female-soiled bedding. Kudwa et al. (2005) concluded that male mice lacking the Esr2 receptor were incompletely defeminized, although they still displayed normal adult male masculinization. The findings suggested that Esr2 may play a role in the development of sexual behavior.
Morani et al. (2006) reported that both male and female Esr2-null mice showed large areas of unexpanded alveoli in their lungs by 5 months of age. Hypoxia, measured by immunohistochemical analysis for Hif1-alpha (HIF1A; 603348) and chemical adducts, was evident in multiple tissues under resting conditions and became more pronounced after exercise. Morani et al. (2006) concluded that ESR2 is necessary for maintenance of extracellular matrix composition in lung and that loss of ESR2 results in abnormal lung structure and systemic hypoxia. They proposed that systemic hypoxia may be responsible for the left and right heart ventricular hypertrophy and systemic hypertension observed in Esr2-null mice.
Using immunohistochemical and Western blot analysis, Meltser et al. (2008) showed that Esr2 was expressed in the cochlea of male and female mice. Esr2 expression protected mice against acoustic trauma that caused temporary hearing loss. Protection appeared to involve the Bdnf (113505) gene, which contains an estrogen-sensitive response element and encodes a neuroprotective peptide.
In a 16.5-year-old 46,XX East African orphan with ovarian dysgenesis (ODG8; 618187), Lang-Muritano et al. (2018) identified heterozygosity for a c.941A-G transition (c.941A-G, NM_001040275.1) in the fifth coding exon of the ESR3 gene, resulting in a lys314-to-arg (K314R) substitution at a highly conserved residue. Functional analysis in ovarian (KGN), breast (MCF7), and bone (U2OS) cells revealed that the K314R mutant is inactive and exerts a dominant-negative effect on wildtype ESR2.
This variant is classified as a variant of unknown significance because its contribution to ovarian dysgenesis has not been confirmed.
In a 15-year-old 46,XY girl with absence of pubertal development, facial dysmorphism, and ocular anomalies mapping to chromosome 14, Baetens et al. (2018) sequenced the candidate gene ESR2 and identified homozygosity for a 3-bp deletion (c.541_543del, GRCh37) in exon 9, resulting in the in-frame deletion of asn181 (N181del). Her unaffected parents and an unaffected 46,XX sister were heterozygous for the deletion, which was not found in 92 ethnically matched control chromosomes or in 320 additional control chromosomes. However, the deletion was reported at very low frequencies in the Exome Sequencing Project, ExAC, and gnomAD databases, in heterozygosity only. The N181del variant showed significantly increased transcriptional activation in E. coli DH10b cells compared to wildtype ESR2; the father appeared as unaffected in the pedigree in the report, but his phenotype was not discussed.
This variant is classified as a variant of unknown significance because its contribution to ovarian dysgenesis has not been confirmed.
In a 24-year-old 46,XY Brazilian woman with primary amenorrhea, absent breast development, and female external genitalia, Baetens et al. (2018) identified heterozygosity for a c.1277T-G transversion (c.1277T-G, GRCh37) in exon 8 of the ESR2 gene, resulting in a leu426-to-arg (L426R) substitution at a highly conserved residue. DNA from family members was not available for segregation analysis, but the variant was not found in 214 Brazilian exomes or the dbSNP, Exome Sequencing Project, ExAC, or gnomAD databases. Functional analysis in E. coli DH10b cells showed higher transcriptional activity with the L426R mutant compared to wildtype ESR2 in the absence of stimulation with an ERS2-specific ligand.
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