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Androgen Receptor Gene (androgen + receptor_gene)
Kinds of Androgen Receptor Gene Selected AbstractsOsteoblast Deletion of Exon 3 of the Androgen Receptor Gene Results in Trabecular Bone Loss in Adult Male Mice,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 3 2007Amanda J Notini Abstract The mechanism of androgen action on bone was studied in male mice with the AR deleted in mature osteoblasts. These mice had decreased trabecular bone volume associated with a decrease in trabecular number, suggesting that androgens may act directly on osteoblasts to maintain trabecular bone. Introduction: Androgens modulate bone cell activity and are important for the maintenance of bone mass. However, the mechanisms by which they exert these actions on bone remain poorly defined. The aim of this study was to investigate the role of androgens acting through the classical androgen receptor (AR) signaling pathways (i.e., DNA-binding dependent pathways) in osteoblasts using male mice in which exon 3 of the AR gene was deleted specifically in mature osteoblasts. Materials and Methods: Mice with a floxed exon 3 of the AR gene were bred with Col 2.3-cre transgenic mice, in which Cre recombinase is expressed in mineralizing osteoblasts. The skeletal phenotype of mutant mice was assessed by histomorphometry and quantitative ,CT at 6, 12, and 32 weeks of age (n = 8 per group). Wildtype, hemizygous exon 3 floxed and hemizygous Col 2.3-cre male littermates were used as controls. Data were analyzed by one-way ANOVA and Tukey's posthoc test. Results: ,CT analysis of the fifth lumbar vertebral body showed that these mice had reduced trabecular bone volume (p < 0.05) at 32 weeks of age compared with controls. This was associated with a decrease in trabecular number (p < 0.01) at 12 and 32 weeks of age, suggesting increased bone resorption. These effects were accompanied by a reduction in connectivity density (p < 0.01) and an increase in trabecular separation (p < 0.01). A similar pattern of trabecular bone loss was observed in the distal femoral metaphysis at 32 weeks of age. Conclusions: These findings show that inactivation of the DNA binding,dependent functions of the AR, specifically in mature osteoblasts in male mice, results in increased bone resorption and decreased structural integrity of the bone, leading to a reduction in trabecular bone volume at 32 weeks of age. These data provide evidence of a role for androgens in the maintenance of trabecular bone volume directly through DNA binding,dependent actions of the AR in mature osteoblasts. [source] Parent,Daughter Transmission of the Androgen Receptor Gene as an Explanation of the Effect of Father Absence on Age of MenarcheCHILD DEVELOPMENT, Issue 4 2002David E. Comings Based on an evolutionary theory of socialization, Belsky and colleagues proposed that girls exposed to a stressful environment, especially when due to father absence in the first 7 years of life, showed an early onset of puberty, precocious sexuality, and unstable relationships as adults. The authors of this article examined an alternative explanation that a variant X,linked androgen receptor (AR) gene, predisposing the father to behaviors that include family abandonment, may be passed to their daughters causing early puberty, precocious sexuality, and behavior problems. The results of a study of 121 White males and 164 White females showed a significant association of the short alleles of the GGC repeat polymorphism of the AR gene with a range of measures of aggression and impulsivity, increased number of sexual partners, sexual compulsivity, and lifetime number of sex partners in males; and paternal divorce, father absence, and early age of menarche in females. These findings support a genetic explanation of the Belsky psychosocial evolutionary hypothesis regarding the association of fathers' absence and parental stress with early age of onset of menarche and early sexual activity in their daughters. A genetic explanation of the father absence effect is proposed in which fathers carrying the AR alleles are more likely to abandon a marriage (father absence) and pass those alleles to their daughters in whom they produce an earlier age of menarche and behavioral problems. [source] Association of non-alcoholic steatohepatitis (NASH) with chronic neutrophilic leukemiaEUROPEAN JOURNAL OF HAEMATOLOGY, Issue 3 2004Chikashi Yoshida Abstract: A 54-yr-old female having chronic neutrophilic leukemia (CNL) associated with severe liver injury is presented. Physical examination on admission showed severe jaundice, hepatosplenomegaly, massive ascites, and pretibial edema. Complete blood count showed a hemoglobin level of 9.1 g/dL, platelet count of 25.8 × 104/,L, and white blood cell count of 36.6 × 103/,L with 89.7% neutrophils. Blood chemistry showed hyperbilirubinemia (21.9 mg/dL) with normal transaminase levels. There was no abnormality in serum cholesterol, triglyceride, or glucose levels. Neutrophil alkaline phosphatase activity was significantly elevated. Bone marrow aspiration showed myeloid hyperplasia with normal karyotype. Rearrangement of the bcr/abl was not detected by either polymerase chain reaction or fluorescence in situ hybridization. Human androgen receptor gene assay (HUMARA) of the bone marrow cells showed clonal proliferation of neutrophils. The patient was diagnosed as having CNL. To evaluate the pathogenesis of the liver injury, a needle biopsy was performed, which showed steatohepatitis with infiltration of neutrophils. As the patient had no history of alcohol abuse, a diagnosis of non-alcoholic steatohepatitis (NASH) was made. Assuming that the infiltration of abnormal neutrophils into the liver contributed to the development of NASH, she was treated with cytoreductive chemotherapy (cytosine arabinoside: 100 mg/d, 1,3 doses/wk). With decreases in white blood cell counts, serum bilirubin levels decreased gradually to 1.5 mg/mL. A postchemotherapy liver biopsy specimen showed marked improvement of the fatty degenerative change. To our knowledge, this is the first report describing the development of NASH in a myeloproliferative disorder. We believe that the infiltration of leukemic cells contributed to the development of NASH in this patient. [source] Lyonization pattern of normal human nailsGENES TO CELLS, Issue 5 2008Mariko Okada To examine the X-inactivation patterns of normal human nails, we performed the human androgen receptor gene assay of DNA samples extracted separately from each finger and toe nail plates of nine female volunteers. The X-inactivation pattern of each nail was unique and constant for at least 2 years. The frequency of nails with one of the two X-chromosomes exclusively inactivated was 25.9%. In the nails composed of two types of cells with either one X-chromosome inactivated, the two cell types were distributed in patchy mosaics. These findings suggest that the composition of precursor cells of each nail is maintained at each site at least through several cycles of regeneration time, and that the nail plate has a longitudinal band pattern, each band consisting of cells with only one of the two X-chromosomes inactivated. Using the frequency of nails with one of two X-chromosomes exclusively inactivated, we estimated the number of progenitor cells that gave rise to the nail plate during development to be about 3, under the assumption that the process follows the binominal distribution model. A strong correlation observed among the big, index and little fingers, and among the corresponding toes suggests an interesting interpretation concerning their morphogenetic process. [source] The CAG repeat polymorphism within the androgen receptor gene and maleness,INTERNATIONAL JOURNAL OF ANDROLOGY, Issue 2 2003Michael Zitzmann Summary The androgen testosterone and its metabolite dihydrotestosterone exert their effects on gene expression and thus effect maleness via the androgen receptor (AR). A diverse range of clinical conditions starting with complete androgen insensitivity has been correlated with mutations in the AR. Subtle modulations of the transcriptional activity induced by the AR have also been observed and frequently assigned to a polyglutamine stretch of variable length within the N-terminal domain of the receptor. This stretch is encoded by a variable number of CAG triplets in exon 1 of the AR gene located on the X chromosome. First observations of pathologically elongated AR CAG repeats in patients with X-linked spino-bulbar muscular atrophy showing marked hypoandrogenic traits were supplemented by partially conflicting findings of statistical significance also within the normal range of CAG repeat length: an involvement of prostate tissue, spermatogenesis, bone density, hair growth, cardiovascular risk factors and psychological factors has been demonstrated. The highly polymorphic nature of glutamine residues within the AR protein implies a subtle gradation of androgenicity among individuals within an environment of normal testosterone levels providing relevant ligand binding to ARs. This modulation of androgen effects may be small but continuously present during a man's lifetime and, hence, exerts effects that are measurable in many tissues as various degrees of androgenicity and represents a relevant effector of maleness. It remains to be elucidated whether these insights are important enough to become part of individually useful laboratory assessments. [source] Androgen insensitivity and male infertility,INTERNATIONAL JOURNAL OF ANDROLOGY, Issue 1 2003O. Hiort Summary Abnormal human spermatogenesis can be caused by defects in androgen action because of androgen insensitivity. A variety of mutations have been described in the human androgen receptor gene associated with male infertility. These can be attributed to two molecular mechanisms. First, point mutations in the androgen receptor gene cause alterations in the amino acid sequence and, hence, lead to apparently slight changes in the androgen receptor effector mechanisms and mild androgen insensitivity. Secondly, variations in the polymorphic poly glutamine segment within the N-terminal end of the androgen receptor have been ascribed to correlate with fertility aspects possibly because of modifications of transcriptional regulatory mechanisms. It has been postulated that longer poly glutamine segments are associated with decreased sperm counts. However, the molecular mechanisms that lead to inhibition of spermatogenesis because of a mutated androgen receptor are poorly understood and will need more focus in the future. [source] Molecular basis for the antiandrogen withdrawal syndromeJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 1 2004Hiroshi Miyamoto Abstract In patients with prostate cancer who manifest disease progression during combined androgen blockade therapy, discontinuation of antiandrogen treatment might result in prostate-specific antigen decline, often associated with clinical improvement. The response called antiandrogen withdrawal syndrome is thus acknowledged as a general phenomenon. However, molecular mechanisms responsible for this syndrome are not completely understood. This article outlines the proposed mechanisms, including alterations of androgen receptor gene and its coregulatory proteins and activation of the signal transduction pathway, and the potential therapeutic approaches based on the specific mechanisms. © 2003 Wiley-Liss, Inc. [source] Clonal analysis of cutaneous fibrous histiocytoma (dermatofibroma)JOURNAL OF CUTANEOUS PATHOLOGY, Issue 7 2002Pei Hui Background:, Dermatofibroma (DF) or cutaneous fibrous histiocytoma is a common benign fibrohistiocytic lesion involving the dermis and subcutis. Histologically, it is subclassified into fibroblastic and histiocytoid forms. Its histogenesis is controversial. While often referred to as a neoplastic process, definite evidence of neoplasia in DF has been lacking. Alternatively, some authorities have suggested that DF is a fibrosing inflammatory process. Diagnostically, the most important question faced is the distinction from dermatofibrosarcoma protuberans (DFSP). Misdiagnosis can occur, as the early phase of DFSP can simulate DF, particularly the deep and cellular forms of DF. Methods:, To address this issue, and to investigate whether DF is in fact a neoplasm, we evaluated 31 examples of DF of various histological types in female patients and assessed clonality by analyzing X-chromosome inactivation as indicated by the methylation status of the androgen receptor gene (HUMARA). Representative cases of DFSP were analyzed for comparison. Results:, Among the selected 31 cases of DF, 24 cases provided intact DNA and informative polymorphism at the AR alleles, including one case of recurrent deep fibrous histiocytoma. Among these 24 cases, randomly inactivated AR alleles were observed in 17 cases including a deep, recurrent fibroblastic DF. A non-random inactivation at AR alleles was observed in seven cases, of which six cases showed either typical histiocytoid form of DF (four cases) or mixed cell types with predominant histiocytoid cell type (two cases). One fibroblastic DF also showed a monoclonal pattern. HUMARA analysis of DFSP revealed non-random inactivation of polymorphic AR alleles. Conclusions:, These findings suggest that DF is a heterogeneous process. Monoclonal genotype was found in DFs with histiocytoid or mixed type with predominant histiocytoid features, suggesting that histiocytoid cells probably represent the neoplastic component. The fibroblastic form of DF may represent a reactive fibroblastic proliferation. Alternatively, it may represent a true neoplasm whose neoplastic cell type has been obscured by prominent reactive fibroblastic component. [source] Walking capacity evaluated by the 6-minute walk test in spinal and bulbar muscular atrophyMUSCLE AND NERVE, Issue 2 2008Yu Takeuchi MD Abstract Spinal and bulbar muscular atrophy (SBMA) is an adult-onset motor neuron disease caused by a CAG repeat expansion in the androgen receptor gene. Because the progression of SBMA is slow, it is plausible to identify biomarkers that monitor disease course for therapeutic development. To verify whether the 6-min walk test (6MWT) is a biomarker of SBMA, we performed the 6MWT in 35 genetically confirmed patients and in 29 age-matched healthy controls. The walk distance covered within 6 min (6MWD) was significantly less in SBMA than it was in controls (323.3 ± 143.9 m and 637.6 ± 94.2 m, respectively; P < 0.001). In test,retest analysis, the intraclass correlation coefficient for the 6MWD was high in SBMA patients (r = 0.982). In a 1-year follow-up the 6MWD significantly decreased at a rate of 11.3% per year. Our observations suggest that the 6MWT is a biomarker that can be used to monitor progression of motor impairment in SBMA. Muscle Nerve, 2008 [source] An unexpected wide population variation of the G1733A polymorphism of the androgen receptor gene: Data on the Mediterranean regionAMERICAN JOURNAL OF HUMAN BIOLOGY, Issue 6 2005E. Esteban The androgen receptor (AR) has been proposed as a candidate gene for several cancers (breast, prostate, uterine endometrium, colon, and esophagus). Ethnicity is considered an associated risk factor for some of these cancers. Several case-control genetic studies have been focused in samples of the main ethnic groups, but little is known about the distribution of risk polymorphisms in current populations with accurate ethnic and/or geographic origins. The A allele of the G1733A polymorphism of the AR gene has been associated with increased risk of prostate cancer. We provide data from this marker in 12 samples from 7 Mediterranean countries such as Spain, Italy (Sardinia), Greece, Turkey, Morocco, Algeria, and Egypt. A sample from Ivory Coast has also been analyzed. The A allele distribution shows a frequency in the Ivory Coast population (65.17%) that contrasts with the low values found in Northern Mediterraneans (mean average value of 13.98%). North African populations present two-times higher frequencies (average value of 27.19%) than Europeans. The wide population variation range found for the A allele strengthens the potential interest of further screening as a baseline to the design of future preventive and population health programs. Am. J. Hum. Biol. 17:690,695, 2005. © 2005 Wiley-Liss, Inc. [source] Brief communication: Familial resemblance in digit ratio (2D:4D)AMERICAN JOURNAL OF PHYSICAL ANTHROPOLOGY, Issue 2 2009Martin Voracek Abstract Familial resemblance in the second-to-fourth digit ratio (2D:4D), a proxy for prenatal androgen action, was studied in 1,260 individuals from 235 Austrian families. In agreement with findings from twin studies of 2D:4D, heritability estimates based on parent,child and full-sib dyad similarity indicated substantial genetic contributions to trait expression (57% for right hand, 48% for left hand 2D:4D). Because twin studies have found nonadditive genetic as well as shared environmental effects on 2D:4D to be negligible or nil, these family-based estimates in all likelihood reflect the narrow-sense (additive genetic) heritability of the trait. Directional (right-minus-left) asymmetry in 2D:4D was only weakly heritable (6%). The pattern of same-sex and different-sex parent,child and full-sib correlations yielded no evidence for X-linked inheritance. This is surprising, considering evidence for associations of male 2D:4D with sensitivity to testosterone (functional variants of the X-linked androgen receptor gene). 2D:4D was particularly strongly heritable through male lines (father,son and brother,brother correlations), thus raising the possibility that Y-linked genes (such as the sex-determining region SRY) might influence 2D:4D expression. Am J Phys Anthropol, 2009. © 2009 Wiley-Liss, Inc. [source] Increased frequency of extremely skewed X chromosome inactivation in juvenile idiopathic arthritisARTHRITIS & RHEUMATISM, Issue 11 2009Elif Uz Objective Juvenile idiopathic arthritis (JIA) is a childhood rheumatic disease of unknown etiology. Two subgroups of JIA, i.e., oligoarticular and polyarticular, are thought to have an autoimmune component, and show a higher female:male ratio. Skewed X chromosome inactivation (XCI) has previously been shown to be associated with scleroderma and autoimmune thyroiditis, 2 autoimmune disorders occurring predominantly in females. This study was undertaken to extend the analysis to the pediatric age group and to determine the XCI profiles of patients with JIA. Methods A polymorphic repeat in the androgen receptor gene was genotyped to determine XCI status in 81 female patients with JIA (21 with polyarticular disease and 60 with oligoarticular disease) and 211 healthy female controls. DNA obtained from venous blood samples was used for this analysis. Results Informative data were obtained on 62 JIA patients and 155 controls. Skewed XCI was observed in 14 patients (22.6%) and 11 controls (7.1%) (P = 0.0036), and extreme skewing was apparent in 8 patients (12.9%) and 2 controls (1.3%) (P = 0.0008). Conclusion Our findings in the present study indicate that skewed XCI may be a risk factor for the occurrence of autoimmune disorders, including JIA. [source] Precise microdissection of human bladder carcinomas reveals divergent tumor subclones in the same tumorCANCER, Issue 1 2002Liang Cheng M.D. Abstract BACKGROUND Human bladder carcinoma is thought to arise from a field change that affects the entire urothelium. Whether independently transformed urothelial cell populations exist in the same patient is uncertain. METHODS We studied the clonality of urinary bladder carcinoma in 18 female patients who underwent cystectomy for urothelial carcinoma. None had multiple tumors. Tumor samples were obtained from different areas of the same tumor. Sixty-seven tumor samples were analyzed. Tumor genomic DNA was microdissected and extracted from formalin-fixed, paraffin-embedded slides. The clonality of urothelial tumors was evaluated on the basis of a polymorphism of the X chromosome-linked human androgen receptor gene (HUMARA) locus. The technique is dependent on digestion of DNA with the methylation-sensitive restriction enzyme HhaI, polymerase chain reaction (PCR) amplification of HUMARA locus, and detection of methylation of this locus. With this method, only the methylated HUMARA allele is selectively amplified by PCR. RESULTS Eleven of 18 patients were informative. Nonrandom inactivation of the X chromosome was found in 9 of the 11 informative patients (82%). Seven patients showed different patterns of nonrandom X chromosome inactivation for tumor samples obtained from different regions of the same tumor. Two patients showed the same pattern of nonrandom X chromosome inactivation in all samples. CONCLUSIONS Some muscle-invasive urothelial carcinomas may arise from independently transformed progenitor urothelial cells, supporting the "field effect" theory for bladder carcinogenesis. Cancer 2002;94:104,10. © 2002 American Cancer Society. [source] | |||||||||||||