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Variants in the estrogen receptor alpha gene and its mRNA contribute to risk for schizophrenia.

ABSTRACT: Estrogen modifies human emotion and cognition and impacts symptoms of schizophrenia. We hypothesized that the variation in the estrogen receptor alpha (ESR1) gene and cortical ESR1 mRNA is associated with schizophrenia. In a small case-control genetic association analysis of postmortem brain tissue, genotype CC (rs2234693) and haplotypes containing the C allele of a single-nucleotide polymorphism (SNP) in intron1 (PvuII) were more frequent in African American schizophrenics (P = 0.01-0.001). In a follow-up family-based association analysis, we found overtransmission of PvuII allele C and a PvuII C-containing haplotype (P = 0.01-0.03) to African American and Caucasian patients with schizophrenia. Schizophrenics with the 'at risk' PvuII genotype had lower ESR1 mRNA levels in the frontal cortex. Eighteen ESR1 splice variants and decreased frequencies of the wild-type ESR1 mRNA were detected in schizophrenia. In one patient, a unique ESR1 transcript with a genomic insert encoding a premature stop codon and a truncated ESR1 protein lacking most of the estrogen binding domain was the only transcript detected. Using a luciferase assay, we found that mRNA encoding a truncated ESR1 significantly attenuates gene expression at estrogen-response elements demonstrating a dominant negative function. An intron 6 SNP [rs2273207(G)] was associated with an ESR1 splice variant missing exon seven. The T allele of another intron 6 SNP was part of a 3' haplotype less common in schizophrenia [rs2273206(T), rs2273207(G), rs2228480(G)]. Thus, the variation in the ESR1 gene is associated with schizophrenia and the mechanism of this association may involve alternative gene regulation and transcript processing.

SUBMITTER: Weickert CS

PROVIDER: S-EPMC2465798 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Estrogen receptor-alpha variants increase risk of Alzheimer's disease in women with Down syndrome.

Project description:Genetic variants that affect estrogen activity may influence the risk of Alzheimer's disease (AD). Two tightly linked polymorphisms (PvuII and XbaI) in the first intron of estrogen receptor 1 (ESR1), the gene for ER-alpha, have been reported to influence estrogen receptor expression and may influence the risk of AD.We examined the relation of polymorphisms in ESR1 to the risk of AD in women with Down syndrome. The subjects (181 women with DS, 41-78 years of age) were followed at 14- to 18-month intervals. Information from cognitive assessments, caregiver interviews, medical record reviews and neurological examinations was used to classify dementia. Genomic DNA was genotyped for 5 single-nucleotide polymorphisms in the upstream region and the first exon/intron of the ESR1 gene. Their association with dementia risk was evaluated, adjusting for covariates.Women with at least 1 copy of the C allele at rs2234693 (PvuII) and those homozygous for the C allele at rs2077647 had an almost 3-fold increase in the risk of AD, compared with women without the C allele. The increased risks were independent of the apolipoprotein E genotype.These findings support a role for estrogen receptor activity in the development of AD in women with Down syndrome.

| S-EPMC2430887 | biostudies-literature

miR-22 inhibits estrogen signaling by directly targeting the estrogen receptor alpha mRNA.

Project description:Estrogen receptor alpha (ER alpha) is a ligand-regulated transcription factor with a broad range of physiological functions and one of the most important classifiers in breast cancer. MicroRNAs (miRNAs) are small noncoding RNAs that have emerged as important regulators of gene expression in a plethora of physiological and pathological processes. Upon binding the 3' untranslated region (UTR) of target mRNAs, miRNAs typically reduce their stability and/or translation. The ER alpha mRNA has a long 3' UTR of about 4.3 kb which has been reported to reduce mRNA stability and which bears evolutionarily conserved miRNA target sites, suggesting that it might be regulated by miRNAs. We have performed a comprehensive and systematic assessment of the regulatory role of all miRNAs that are predicted to target the 3' UTR of the ER alpha mRNA. We found that miR-22 represses ER alpha expression most strongly and by directly targeting the ER alpha mRNA 3' UTR. Of the three predicted miR-22 target sites in the 3' UTR, the evolutionarily conserved one is the primary target. miR-22 overexpression leads to a reduction of ER alpha levels, at least in part by inducing mRNA degradation, and compromises estrogen signaling, as exemplified by its inhibitory impact on the ER alpha-dependent proliferation of breast cancer cells.

| S-EPMC2698751 | biostudies-literature

Blockade of estrogen action upregulates estrogen receptor-alpha mRNA in the fetal brain.

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| S-EPMC2793321 | biostudies-literature

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| S-EPMC2613912 | biostudies-literature

Estrogen receptor α gene polymorphisms and risk of Alzheimer's disease: evidence from a meta-analysis.

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Association of estrogen receptor alpha gene polymorphism with age at onset, general psychopathology symptoms, and therapeutic effect of schizophrenia.

Project description:BACKGROUND: Estrogen is believed to play an important role in the central nervous system (CNS) and exert a protective role against schizophrenia. Estrogen receptor alpha (ESR?) mediates the biological action of estrogen. Rs2234693 and rs9340799, single nucleotide polymorphisms of ESR?, may be related to many psychiatric disorders, while their association with schizophrenia has not been clarified. METHODS: Genotypes rs2234693 and rs9340799 were detected in 303 schizophrenic patients and 292 healthy controls in a Chinese population. The positive and negative syndrome scale (PANSS) was used to estimate symptoms and therapeutic effects. The association of these polymorphisms with schizophrenia and clinical characteristics was analyzed by the chi-square test, analysis of variance, and others. RESULTS: The distribution of genotypes and allele frequencies of rs2234693 and rs9340799 exhibited no significant differences between patients and controls, while haplotypes consisting of these polymorphisms had significant differences. For 2234693, T-allele carriers had an earlier age at onset. CC-homozygote carriers had a higher general psychopathology score and its percentage reduction in male and paranoid patients, respectively. CC-homozygote carriers had a higher tension (G4) and poor impulse control (G14) score, mainly in paranoid patients. Furthermore, patients with the CC homozygote had higher reductions of G4 and G14 scores when treated by aripirazole and risperidone, respectively. CONCLUSIONS: Haplotypes consisting of these two polymorphisms in ESR? may be strongly associated with schizophrenia. The rs2234693 was related to age at onset, general psychopathology, G4 and G14 symptoms, even the therapeutic effect in different groups.

| S-EPMC3608973 | biostudies-literature

Progesterone Receptor Gene Variants in Metastatic Estrogen Receptor Positive Breast Cancer.

Project description:Tumor mutations in the gene encoding estrogen receptor alpha (ESR1) have been identified in metastatic breast cancer patients with endocrine therapy resistance. However, relatively little is known about the occurrence of mutations in the progesterone receptor (PGR) gene in this population. The study objective was to determine the frequency and prognostic significance of tumor PGR mutations for patients with estrogen receptor (ER)-positive metastatic breast cancer. Thirty-five women with metastatic or locally recurrent ER+ breast cancer were included in this IRB-approved, retrospective study. Targeted next-generation sequencing of the PGR gene was performed on isolated tumor DNA. Associations between mutation status and clinicopathologic factors were analyzed as well as overall survival (OS) from time of metastatic diagnosis. The effect of the PGR variant Y890C (c.2669A>G) identified in this cohort on PR transactivation function was tested using ER-PR- (MDA-MB-231), ER+PR+ (T47D), and ER+PR- (T47D PR KO) breast cancer cell lines. There were 71 occurrences of protein-coding PGR variants in 67% (24/36; 95% CI 49-81%) of lesions. Of the 49 unique variants, 14 are single nucleotide polymorphisms (SNPs). Excluding SNPs, the median OS of patients with PGR variants was 32 months compared to 79 months with wild-type PGR (p = 0.42). The most frequently occurring (4/36 lesions) non-SNP variant was Y890C. Cells expressing Y890C had reduced progestin-stimulated PR transactivation compared to cells expressing wild-type PR. PGR variants occur frequently in ER+ metastatic breast cancer. Although some variants are SNPs, others are predicted to be functionally deleterious as demonstrated with Y890C PR.

| S-EPMC7152560 | biostudies-literature

Association between estrogen receptor-alpha gene PvuII and XbaI polymorphisms and osteoarthritis risk: a meta-analysis.

Project description:Estrogen receptor-alpha (ER-α) gene PvuII (T/C) and XbaI (A/G) polymorphisms have been hypothesized to be associated with osteoarthritis (OA) risk by several epidemiological studies, however, the available results were inconclusive and conflicting. We conducted a meta-analysis of 10 case-control studies that included 3328 osteoarthritis cases and 6390 case-free controls. We assessed the strength of the association, using odds ratios (ORs) with 95% confidence intervals (CIs). This meta-analysis showed that the ER-α PvuII and XbaI polymorphisms were not associated with OA risk in overall population. For the PvuII (T/C) polymorphism, however, in the subgroup analysis by country, a significantly reduced risk was observed among Chinese (TC vs. CC: OR = 0.73, 95% CI 0.54-0.99, I (2) = 0%, P heterogeneity = 0.498; dominant model, OR = 0.73, 95% CI = 0.55-0.98, I (2) = 0%, P heterogeneity = 0.555). For the XbaI (A/G) polymorphism, when stratifying by sample size, a significantly elevated risk was found in sample size ≤ 500 (AA vs. GG: OR = 2.60, 95% CI 1.10-6.18, I (2) = 42.9%, P heterogeneity = 0.135; dominant model: OR = 2.04, 95% CI 1.12-3.71, I (2) = 11.4%, P heterogeneity = 0.341; and recessive model: OR = 1.69, 95% CI 1.12-2.55, I (2) = 40.2%, P heterogeneity = 0.154). No publication bias was found in the present study. This meta-analysis suggests that ER-α PvuII (T/C) polymorphism may be associated with a reduced OA risk among Chinese and the XbaI (A/G) polymorphism may not be associated with OA risk, while the observed increase in OA risk for XbaI polymorphism may be due to small-study bias.

| S-EPMC4402771 | biostudies-literature

Estrogen receptor alpha polymorphisms and postmenopausal breast cancer risk.

Project description:BACKGROUND: The estrogen receptor alpha (ESR1) is a mediator of estrogen response in the breast. The most studied variants in this gene are the PvuII and XbaI polymorphisms, which have been associated to lower sensitivity to estrogen. We evaluated whether these polymorphisms were associated with breast cancer risk by means of an association study in a population of Caucasian postmenopausal women from the Rotterdam study and a meta-analysis of published data. METHODS: The PvuII and XbaI polymorphisms were genotyped in 3,893 women participants of the Rotterdam Study. Baseline information was obtained through a questionnaire. We conducted logistic regression analyses to assess the risk of breast cancer by each of the ESR1 genotypes. Meta-analyses of all publications on these relations were done by retrieving literature from Pubmed and by further checking the reference lists of the articles obtained. RESULTS: There were 38 women with previously diagnosed breast cancer. During follow-up, 152 were additionally diagnosed. The logistic regression analyses showed no difference in risk for postmenopausal breast cancer in carriers of the PvuII or XbaI genotypes neither in overall, incident or prevalent cases. No further evidence of a role of these variants was found in the meta-analysis. CONCLUSIONS: Our results suggest that the ESR1 polymorphisms do not play a role in breast cancer risk in Caucasian postmenopausal women.

| S-EPMC2217623 | biostudies-other

17Beta-estradiol regulation of the mRNA expression of T-type calcium channel subunits: role of estrogen receptor alpha and estrogen receptor beta.

Project description:Low-voltage-activated (T-type) calcium channels are responsible for burst firing and transmitter release in neurons and are important for exocytosis and hormone secretion in pituitary cells. T-type channels contain an alpha1 subunit, of which there are three subtypes, Cav3.1, -3.2, and -3.3, and each subtype has distinct kinetic characteristics. Although 17beta-estradiol (E2) modulates T-type calcium channel expression and function, little is known about the molecular mechanisms involved. We used real-time PCR quantification of RNA extracted from hypothalamic nuclei and pituitary in vehicle and E2-treated C57BL/6 mice to elucidate E2-mediated regulation of Cav3.1, -3.2, and -3.3 subunits. The three subunits were expressed in both the hypothalamus and the pituitary. E2 treatment increased the mRNA expression of Cav3.1 and -3.2, but not Cav3.3, in the medial preoptic area and the arcuate nucleus. In the pituitary, Cav3.1 was increased with E2 treatment, and Cav3.2 and -3.3 were decreased. To examine whether the classical estrogen receptors (ERs) were involved in the regulation, we used ERalpha- and ERbeta-deficient C57BL/6 mice and explored the effects of E2 on T-type channel subtypes. Indeed, we found that the E2-induced increase in Cav3.1 in the hypothalamus was dependent on ERalpha, whereas the E2 effect on Cav3.2 was dependent on both ERalpha and ERbeta. However, the E2-induced effects in the pituitary were dependent on only the expression of ERalpha. The robust E2 regulation of T-type calcium channels could be an important mechanism by which E2 increases the excitability of hypothalamic neurons and modulates pituitary secretion.

| S-EPMC2821194 | biostudies-literature

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