Systematic Mutation Screening of the Estrogen Receptor Beta Gene in Probands of Different Weight Extremes: Identification of Several Genetic Variants

Philipps University of Marburg, Marburg, Hesse, Germany
Journal of Clinical Endocrinology & Metabolism (Impact Factor: 6.21). 01/1999; 83(12):4524-7. DOI: 10.1210/jcem.83.12.5471
Source: PubMed


Estrogens are known to have an inhibitory effect on food intake in rodents and primates. Decreased estrogen levels that are found for instance in menopausal woman and in ovarectomized rodents result in body weight gain. Estrogen can act both in the periphery and in the central nervous system via at least two different estrogen receptors (alpha and beta). We systematically screened the coding region and part of the 5' and 3'regions of the estrogen receptor beta gene (ER beta) in 96 extremely obese children and adolescents, 50 patients with anorexia nervosa (AN), 28 patients with bulimia nervosa (BN), and 25 healthy underweight individuals. We detected five different sequence variants in the ER beta: a) A 21 bp deletion (codons 238 to 244) was detected in two obese probands and an underweight individual. b) An 846G-->A transition leading to a nonconservative amino acid substitution (G-250-S) was found in two obese male probands. Both a) and b) were located within the flexible hinge region between DNA and ligand binding domain. c) For a 1082G-->A polymorphism we found suggestive evidence for an association between the more common 1082G-allele and anorexia nervosa (nominal p=0.04). d) One silent mutation (1421T-->C) was found solely in two obese probands. e) A common variant is located in the 3' nontranslated region at position 1730(A-->G). We did not detect association of this polymorphism to any of the analyzed phenotypes. We conclude that the ER beta harbors several different mutations and polymorphisms, none of which can readily be associated with the phenotypes under study.

Download full-text


Available from: John K Young
  • Source
    • "Estrogen signaling in the cell is mediated by estrogen receptors, of which at least two subtypes exist: ERα and ERβ. Recently, several sequence variants of the ERβ gene have been described (Rosenkranz et al., 1998), including the silent RsaI polymorphism that has been overrepresented in ovulatory dysfunctions. This polymorphism comprises the exchange of nucleotide G for nucleotide A at position 1082 in exon 5 of the ERβ gene, on the long arm of chromosome 14 (Sundarrajan et al., 2001). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The estrogen receptor β (ERβ) gene plays an important role in the regulation of fertility in both males and females. The RsaI polymorphism in ERβis associated with male infertility in Caucasian patients. The aim of this study was to investigate the frequency of this polymorphism in the etiology of idiopathic male infertility and its correlation with smoking habits. We analyzed 287 Brazilian men, including 161 infertile and 126 fertile men, to evaluate the association between the RsaI polymorphism and male infertility. The RsaI variant alleles of all patients were determined by allele-specific polymerase chain reaction. Compared with a control group (normozoospermic men), the frequency of the RsaI AG-genotype was four times higher in infertile men (P = 0.01), five times higher in azoospermic men (P = 0.02), and seven times higher in teratozoospermic men (P = 0.001). The frequency of the RsaI AG-genotype was three times higher in infertile smokers (P = 0.038) compared with infertile nonsmokers, and nine times higher in azoospermic smokers (P = 0.035) compared with azoospermic nonsmokers. The RsaI polymorphism in ERβmay have modulating effects on human spermatogenesis. There seems to be a consistent association between RsaI polymorphism and smoking habits in infertile men.
    Preview · Article · Sep 2015 · Genetics and molecular research: GMR
  • Source
    • "In 1998, Tsukamoto et al. first characterized the CA repeat polymorphism (D14S1026) of the ERβ gene in a Japanese population [14]. A systematic mutation screening subsequently detected five different sequence variants, including two mutations and three polymorphisms [15]. Importantly, in an in vitro functional analysis, the presence of the valine in position 320 showed significantly decreased maximal transcriptional activity [16]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Keishibukuryogan (KBG; Guizhi-Fuling-Wan in Chinese) is one of the Kampo (Japanese traditional) medicines used to treat patients with climacteric syndrome. KBG can be used by patients who cannot undergo hormone replacement therapy due to a history of breast cancer. We evaluated whether cytosine-adenine (CA) repeat polymorphism of the estrogen receptor β gene can be a predictor of the beneficial effect of KBG on climacteric syndrome. We also investigated the relationship between CA repeat polymorphism, the patients' profiles, and the therapeutic effect. We found that CA was an SS, SL, or LL genotype according to the number of repeats. We studied 39 consecutive patients with climacteric disorders who took KBG for 12 weeks. The diagnosis of climacteric disorders was made on the basis of the Kupperman index. KBG significantly improved the patients' climacteric symptoms (i.e., vasomotor symptoms in the patients with the LL genotype and melancholia in the patients with the SL genotype). No relationship between the patients' profiles and CA repeat polymorphism was recognized. CA repeat polymorphism could thus be a potential biomarker to predict the efficacy of KBG in climacteric syndrome, and its use will help to reduce the cost of treating this syndrome by focusing the administration of KBG on those most likely to benefit from it.
    Full-text · Article · Jan 2014 · Evidence-based Complementary and Alternative Medicine
  • Source
    • "ER-β is a member of the steroid receptor superfamily, and detectable levels of ER-β messenger ribonucleic acid (mRNA) and protein have been detected in the rodent uterus and vagina.22–24 The expression of ER-β was investigated using various procedures such as Northern blotting, reverse transcription polymerase chain reaction (RT-PCR), and in situ hybridization, and a prominent expression was found to exist in tissues such as the prostate, ovary, epididymis, testis, bladder, uterus, lung, thymus, colon, small intestine, pituitary, hypothalamus, cerebellum, and brain cortex.21,25–28 ER-β has been reported to modulate the activities of ER-α in the uterus;29 therefore, studying the activity of bioactive compounds on this particular receptor in the uterus will give more convincing clues to understanding their activity. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The expression of genes regulated by estrogen in the uterus was studied in ovariectomized (OVX) rats treated with germinated brown rice (GBR) bioactives, and compared to Remifemin or estrogen at different doses to identify the regulation of these genes in the uterus and their molecular mechanisms. Rats were treated orally with GBR bioactives (phenolics), acylated steryl glucosides (ASG), γ-amino butyric acid (GABA), and γ-oryzanol (ORZ) at 100 and 200 mg/kg, Remifemin (REM) at 10 mg/kg and 20 mg/kg, or estrogen (EST) at 0.2 mg/kg. Ribonucleic acid (RNA) was extracted from the uterus, and messenger (m)RNA expression of selected genes encoding estrogen receptor-beta (ER-β), calcium-binding protein (CaBP9k), complement protein (C3), heat shock protein 70 kDa (HSP70), and interleukin (IL)-4 receptor were quantified. Similarly, serum steroid hormone concentration was monitored at 2, 4, and 8 weeks after treatments. ER-β antibody binding to the uterus sections was also studied using immunohistochemistry. The group treated with EST (0.2 mg/kg) upregulated ER-β, C3, and IL-4 receptor genes compared to other groups (P<0.001). GBR phenolics (200 mg/kg) treatment upregulated the ER-β gene almost to the level of the sham non-treated group. The CaBP9k gene showed upregulation in groups treated with ASG (200 mg/kg), EST (0.2 mg/kg), and ORZ (200 mg/kg) (P<0.05). Estrogen levels increased in groups treated with EST, ASG, and ORZ (200 mg/kg) compared to the OVX untreated group (P<0.05), and there was a slight non-significant decrease (P>0.05) in the progesterone levels in the OVX untreated group compared to the sham and other treated groups. There was a significant increase at 8 weeks in the level of FSH (P<0.05) in the treated groups compared to the OVX untreated group. There was no significant difference (P>0.05) in serum luteinizing hormone (LH) between the OVX untreated group and other groups. The sham and GBR phenolics treated group showed ER-β reactivity at the glandular epithelium, while the group treated with EST showed immunoreactivity at the glandular, luminal, and stromal epithelium. GBR phenolics moderately regulate the expression of ER-β, HSP70, and IL-4 receptor genes, and gave a positive immunoreaction to ER-β antigen in the uterus. ASG regulates the expression of CaBP9k and IL-4 receptor genes, and ORZ regulates the expression of the CaBP9k gene, while GABA at 100 mg/kg regulates the expression of the HSP70 gene. GBR and its bioactives might have an effect on estrogen-regulated genes in the uterus of rats.
    Full-text · Article · Dec 2013 · Drug Design, Development and Therapy
Show more