Mutations in the X-linked androgen receptor (AR) gene cause androgen insensitivity syndrome (AIS), resulting in an impaired embryonic sex differentiation in 46,XY genetic men. Complete androgen insensitivity (CAI...Mutations in the X-linked androgen receptor (AR) gene cause androgen insensitivity syndrome (AIS), resulting in an impaired embryonic sex differentiation in 46,XY genetic men. Complete androgen insensitivity (CAIS) produces a female external phenotype, whereas cases with partial androgen insensitivity (PALS) have various ambiguities of the genitalia. Mild androgen insensitivity (MAIS) is characterized by undermasculinization and gynecomastia. Here we describe a 2-month-old 46,XY female patient, with all of the characteristics of CAIS. Defects in testosterone (T) and dihydrotestosterone (DHT) synthesis were excluded. Sequencing of the AR gene showed the presence in exon 6 of a T to C transition in the second base of codon 790, nucleotide position 2369, causing a novel missense Leu790Pro mutation in the ligand-binding domain of the AR protein. The identification of a novel AR mutation in a girl with CAIS provides significant information due to the importance of missense mutations in the ligand-binding domain of the AR, which are able to induce functional abnormalities in the androgen binding capability, stabilization of active conformation, or interaction with coactivators.展开更多
The aim of this study was to examine whether CAG/GGN repeats are significant modulators of serum concentrations of total and free testosterone(T)as well as of luteinizing hormone(LH)in elderly men.Sixty-nine 60-to 80-...The aim of this study was to examine whether CAG/GGN repeats are significant modulators of serum concentrations of total and free testosterone(T)as well as of luteinizing hormone(LH)in elderly men.Sixty-nine 60-to 80-year-old men with subnormal T levels(≤11.0 nmol L^(-1))and 104 men with normal T levels taking part in a nested case-control study were used for these analyses.Sex hormones were measured and free T was calculated.The CAG and GGN polymorphisms in the androgen receptor gene were determined by polymerase chain reaction and subsequent direct sequencing.There were no differences in the CAG and GGN repeat lengths between the groups.In cross-sectional analyses of the whole cohort,total and free T were positively associated with CAG length(all P<0.05)before,but not after,waist circumference or body mass index was added to the model.CAG repeat lengths were weakly,but not independently,associated with total and free T.These findings indicate that when clinically evaluating T and LH levels in elderly men,the CAG and GGN repeat lengths do not need to be taken into consideration.展开更多
We aimed to determine the mechanisms of the anabolic actions of androgens in skeletal muscle by investigating potential androgen receptor (AR)-regulated genes in in vitro and in vivo models. The expression of the my...We aimed to determine the mechanisms of the anabolic actions of androgens in skeletal muscle by investigating potential androgen receptor (AR)-regulated genes in in vitro and in vivo models. The expression of the myogenic regulatory factor myogenin was significantly decreased in skeletal muscle from testosterone-treated orchidectomized male mice compared to control orchidectomized males, and was increased in muscle from male AR knockout mice that lacked DNA binding activity (AR△ZF2) versus wildtype mice, demonstrating that myogenin is repressed by the androgen/AR pathway. The ubiquitin ligase Fbxo32 was repressed by 12 h dihydrotestosterone treatment in human skeletal muscle cell myoblasts, and c-Myc expression was decreased in testosterone-treated orchidectomized male muscle compared to control orchidectomized male muscle, and increased in AR△ZF2 muscle. The expression of a group of genes that regulate the transition from myoblast proliferation to differentiation, Tceal7, p57Kip2, IEf2 and calcineurin Aa, was increased in AR△ZF2 muscle, and the expression of all but p57kip2 was also decreased in testosterone-treated orchidectomized male muscle compared to control orchidectomized male muscle. We conclude that in males, androgens act via the AR in part to promote peak muscle mass by maintaining myoblasts in the proliferative state and delaying the transition to differentiation during muscle growth and development, and by suppressing ubiquitin ligase-mediated atrophy pathways to preserve muscle mass in adult muscle.展开更多
BACKGROUND Androgen insensitivity syndrome is an X-linked recessive genetic disease caused by mutations in the androgen receptor gene(AR).However,the underlying molecular mechanisms for the majority of AR variants rem...BACKGROUND Androgen insensitivity syndrome is an X-linked recessive genetic disease caused by mutations in the androgen receptor gene(AR).However,the underlying molecular mechanisms for the majority of AR variants remain unclear.In this study,we identified a point variant in three patients with complete androgen insensitivity syndrome(CAIS),summarized the correlation analysis,and performed a literature review.CASE SUMMARY The proband was raised as a girl.In infancy,she was first referred to hospital with a right inguinal hernia.Ultrasonography revealed the absence of a uterus and ovaries,and a testis-like structure located at the inguinal canal.Further diagnostic workup detected a 46,XY karyotype,and fluorescence in situ hybridization analysis showed the presence of the SRY gene.Histological analysis revealed the excised tissue to be testicular.Twelve years later,she was admitted to our hospital with a lack of breast development.Her pubic hair and breasts were Tanner stage I.She had normal female external genitalia.Blood hormone tests showed normal testosterone levels,low estradiol levels,and high gonadotropin levels.Her two siblings underwent similar examinations,and all three had a rare hemizygous missense mutation in AR:c.2678C>T.In vitro functional analyses revealed decreased nuclear translocation in AR-c.2678C>T mutation cells.CONCLUSION This case of CAIS was caused by an AR variant(c.2678C>T).Functional studies showed impaired nuclear translocation ability of the mutant protein.展开更多
Objective:To explore the relation between the polymorphism of repetitive sequence in gene CAG of androgen receptor(AR)and the susceptibility and clinical stages as well as pathological grading of prostate cancer among...Objective:To explore the relation between the polymorphism of repetitive sequence in gene CAG of androgen receptor(AR)and the susceptibility and clinical stages as well as pathological grading of prostate cancer among Han population.Method:Sixty-eight cases with prostate cancer hospitalized in Urinary Surgery Department from Feb.2010 to Feb.2012 and 60 healthy cases were chosen as research subjects.Methods of PCR and direct sequencing were adopted to detect DNA sequence of AR gene and the length of repetitive sequence in CAG.Results:The lengths of repetitive sequence in CAG of patients with prostate cancer and healthy people were(22.3±4.6)and(23.0±4.9),respectively showing no statistical significance.Comparing length(repetitive sequence of CAG)>22,those with that<22 suffer a remarkably higher risk of prostate cancer(P<0.05).The number of repetitive sequence in CAG of patients at clinical stage C-D was less than that of patients at stage B,and the number of repetitive sequence in CAG of patients with poorly differentiated prostate cancer was also less than that of patients with moderately and highly differentiated prostate cancer.But there was no statistical significance int the difference(P>0.05);the proportion of patients with length<22 at clinical stage C-D was much larger than that of patients at clinical stage B(P<0.05),and as the aggravation of pathological grading,the proportion of patients with the length<22 was also remarkably increased and there was significant difference between patients with highly differentiated prostate cancer and those with poorly differentiated prostate cancer(P<0.05).Conclusions:There is correlation between the occurrence and development of prostate cancer in Han population and the polymorphism of repetitive sequence in gene CAG of androgen receptor.The less the number of repetitive sequence in CAG is,the higher the risk of prostate cancer will be and the more severe the clinical stage and pathological grading will be.展开更多
To further investigate the molecular mechanism of androgen insensitivity syndromes (AIS), exons B to H of the androgen receptor (AR) gene in seven Chinese patients with Complete AlS (CAIS) were examined by the polymer...To further investigate the molecular mechanism of androgen insensitivity syndromes (AIS), exons B to H of the androgen receptor (AR) gene in seven Chinese patients with Complete AlS (CAIS) were examined by the polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) analysis and direct DNA sequencing. Four distinct point mutations (Gly743Arg, Va1866Met, Arg752Gln, T2919→deletion) were identified in 4patients, and all the mutations were localized in exons E or G encoding androgen binding domain of AR. The frame-shift mutation caused by deletion of T2919 had not been reported yet so far, therefore, It was a novel mutation. Detection of the AR gene in 2 mothers showed both of them were heterozygotes carrying the same mutationsas their daughters. our study was helpful for further delineating the diversity of genetic alterations of the AR gene in patients with AlS and better understanding the relationships between structure and function of AR.展开更多
The mechanism of antifertility effect of testosterone undecanoate on male rat was investigated. Eight 12-week old rats were injected with 20 mg/kg of testosterone undecanoate at bi--week intervals for 3 months. As com...The mechanism of antifertility effect of testosterone undecanoate on male rat was investigated. Eight 12-week old rats were injected with 20 mg/kg of testosterone undecanoate at bi--week intervals for 3 months. As compared to that in the 10 control rafs, the sperm density in testis rete fluid of the treatment rats declined by 7%, the motility of sperm from epididymis cauda reduced to 6%. While the testosterone level in serum increased to 255 %, the testosterone level in testis rete fluid decreased to 55%. All of these differences were significant. The androgen receptor gene expression in the testis and epididymis was suppressed in the treatment group. The decrease in output of the sperm and sperm motility of epididymis cauda may be due to the reduced testosterone production by Leydig cells and suppression of androgen receptor gene expression in testis and epididymis.展开更多
2M NaCl-insoluble fraction of rat ventral prostatechromatin(residual proteins)contain proteins able tointeract specifically with androgen-receptor complex andis,therefore,a part of the acceptor complex.Amongresidual p...2M NaCl-insoluble fraction of rat ventral prostatechromatin(residual proteins)contain proteins able tointeract specifically with androgen-receptor complex andis,therefore,a part of the acceptor complex.Amongresidual proteins,a 97 KDa protein has been found whichbinds signifieantly to a genomic fragment containingan androgen-regulated gene coding for a 22 KDa protein.The biological significance of this binding in androgenaction need to be further studied. A mini-plasmid clone containing 22 KDa proteincoding sequence was cloned into Charon 4A genomiclibrary from which a 5.7 Kb genomic fragment wasisolated,identified by hybridization with a 5’ and a 3’cDNA probes,and shown to contain the 5’ flankingsequence.Restriction enzyme treatment of this fragmentyielded a 4.7 Kb restriction fragment representingthe 5’ upstream region and a 1.0 Kb containing part ofthe coding sequence.Deletion studies indicated that the97 KDa protein bound only to a subclone of about 300 bpsegment.Furthermore,gel shifting experiment supportedits DNA-prptein binding.展开更多
Aim:To investigate the involvement of the prostate androgen-regulated(PAR)gene in the androgen receptor(AR) signaling pathway and the malignant phenotype of androgen-independent prostate cancer(PCa)cells.Methods:The d...Aim:To investigate the involvement of the prostate androgen-regulated(PAR)gene in the androgen receptor(AR) signaling pathway and the malignant phenotype of androgen-independent prostate cancer(PCa)cells.Methods:The difference in PAR expression between LNCaP and PC3 cells was detected by reverse transcription-polymerase chain reaction(RT-PCR).Androgen and anti-androgen effects on PAR expression were evaluated by RT-PCR in LNCaP,PC3 cells and PC3 cells stably transfected with vector containing wild-type AR.To determine the importance of PAR in the malignant proliferation of androgen-independent PCa cells,we used small interfering RNA(siRNA)transfection to knock down the expression of the gene in PC3 cells.The changes in the malignant phenotype of PCa cells after transfection were analyzed by cell count,colony formation in soft agar and flow cytometry.Results:PAR expression was 3-fold higher in PC3 cells than that in LNCaP cells.Dihydrotestosterone(DHT)regulated PAR mRNA expression in LNCaP cells and the effect was inhibited by the AR antagonist,flutamide.By contrast,DHT did not affect PAR expression in PC3 cells.The reintroduction of AR into PC3 cells by stable transfection restored the androgen effect on PAR upregulation. After the knockdown of the PAR gene by siRNA,PC3 cells exhibited a reversal of the malignant phenotype.Conclusion: Because of the possibility that PAR is downstream from the AR,and because of its contribution to malignant proliferation in androgen-independent PCa cells,the gene could be a potential therapeutic target for androgen-independent PCa with AR signaling pathway alteration.(Asian J Andro12006 Jul;8:455-462)展开更多
文摘Mutations in the X-linked androgen receptor (AR) gene cause androgen insensitivity syndrome (AIS), resulting in an impaired embryonic sex differentiation in 46,XY genetic men. Complete androgen insensitivity (CAIS) produces a female external phenotype, whereas cases with partial androgen insensitivity (PALS) have various ambiguities of the genitalia. Mild androgen insensitivity (MAIS) is characterized by undermasculinization and gynecomastia. Here we describe a 2-month-old 46,XY female patient, with all of the characteristics of CAIS. Defects in testosterone (T) and dihydrotestosterone (DHT) synthesis were excluded. Sequencing of the AR gene showed the presence in exon 6 of a T to C transition in the second base of codon 790, nucleotide position 2369, causing a novel missense Leu790Pro mutation in the ligand-binding domain of the AR protein. The identification of a novel AR mutation in a girl with CAIS provides significant information due to the importance of missense mutations in the ligand-binding domain of the AR, which are able to induce functional abnormalities in the androgen binding capability, stabilization of active conformation, or interaction with coactivators.
基金the Swedish Research Council(Grant Nos.521-2004-6072 and K2005-72X-14545-03A)the Swedish Cancer Society(Grant Nos.4857-B05-03XCC,070482 and 070139)the Gunnar Nilsson Cancer Fund and the Center for Research in the Elderly in Tromsø,Norway.
文摘The aim of this study was to examine whether CAG/GGN repeats are significant modulators of serum concentrations of total and free testosterone(T)as well as of luteinizing hormone(LH)in elderly men.Sixty-nine 60-to 80-year-old men with subnormal T levels(≤11.0 nmol L^(-1))and 104 men with normal T levels taking part in a nested case-control study were used for these analyses.Sex hormones were measured and free T was calculated.The CAG and GGN polymorphisms in the androgen receptor gene were determined by polymerase chain reaction and subsequent direct sequencing.There were no differences in the CAG and GGN repeat lengths between the groups.In cross-sectional analyses of the whole cohort,total and free T were positively associated with CAG length(all P<0.05)before,but not after,waist circumference or body mass index was added to the model.CAG repeat lengths were weakly,but not independently,associated with total and free T.These findings indicate that when clinically evaluating T and LH levels in elderly men,the CAG and GGN repeat lengths do not need to be taken into consideration.
文摘We aimed to determine the mechanisms of the anabolic actions of androgens in skeletal muscle by investigating potential androgen receptor (AR)-regulated genes in in vitro and in vivo models. The expression of the myogenic regulatory factor myogenin was significantly decreased in skeletal muscle from testosterone-treated orchidectomized male mice compared to control orchidectomized males, and was increased in muscle from male AR knockout mice that lacked DNA binding activity (AR△ZF2) versus wildtype mice, demonstrating that myogenin is repressed by the androgen/AR pathway. The ubiquitin ligase Fbxo32 was repressed by 12 h dihydrotestosterone treatment in human skeletal muscle cell myoblasts, and c-Myc expression was decreased in testosterone-treated orchidectomized male muscle compared to control orchidectomized male muscle, and increased in AR△ZF2 muscle. The expression of a group of genes that regulate the transition from myoblast proliferation to differentiation, Tceal7, p57Kip2, IEf2 and calcineurin Aa, was increased in AR△ZF2 muscle, and the expression of all but p57kip2 was also decreased in testosterone-treated orchidectomized male muscle compared to control orchidectomized male muscle. We conclude that in males, androgens act via the AR in part to promote peak muscle mass by maintaining myoblasts in the proliferative state and delaying the transition to differentiation during muscle growth and development, and by suppressing ubiquitin ligase-mediated atrophy pathways to preserve muscle mass in adult muscle.
基金the key Research and Development Program of Zhejiang Province,No.2020C03121.
文摘BACKGROUND Androgen insensitivity syndrome is an X-linked recessive genetic disease caused by mutations in the androgen receptor gene(AR).However,the underlying molecular mechanisms for the majority of AR variants remain unclear.In this study,we identified a point variant in three patients with complete androgen insensitivity syndrome(CAIS),summarized the correlation analysis,and performed a literature review.CASE SUMMARY The proband was raised as a girl.In infancy,she was first referred to hospital with a right inguinal hernia.Ultrasonography revealed the absence of a uterus and ovaries,and a testis-like structure located at the inguinal canal.Further diagnostic workup detected a 46,XY karyotype,and fluorescence in situ hybridization analysis showed the presence of the SRY gene.Histological analysis revealed the excised tissue to be testicular.Twelve years later,she was admitted to our hospital with a lack of breast development.Her pubic hair and breasts were Tanner stage I.She had normal female external genitalia.Blood hormone tests showed normal testosterone levels,low estradiol levels,and high gonadotropin levels.Her two siblings underwent similar examinations,and all three had a rare hemizygous missense mutation in AR:c.2678C>T.In vitro functional analyses revealed decreased nuclear translocation in AR-c.2678C>T mutation cells.CONCLUSION This case of CAIS was caused by an AR variant(c.2678C>T).Functional studies showed impaired nuclear translocation ability of the mutant protein.
基金supported by special fund for provincial science and technology cooperation project by Science and Technology Department of Henan province(122106000042)
文摘Objective:To explore the relation between the polymorphism of repetitive sequence in gene CAG of androgen receptor(AR)and the susceptibility and clinical stages as well as pathological grading of prostate cancer among Han population.Method:Sixty-eight cases with prostate cancer hospitalized in Urinary Surgery Department from Feb.2010 to Feb.2012 and 60 healthy cases were chosen as research subjects.Methods of PCR and direct sequencing were adopted to detect DNA sequence of AR gene and the length of repetitive sequence in CAG.Results:The lengths of repetitive sequence in CAG of patients with prostate cancer and healthy people were(22.3±4.6)and(23.0±4.9),respectively showing no statistical significance.Comparing length(repetitive sequence of CAG)>22,those with that<22 suffer a remarkably higher risk of prostate cancer(P<0.05).The number of repetitive sequence in CAG of patients at clinical stage C-D was less than that of patients at stage B,and the number of repetitive sequence in CAG of patients with poorly differentiated prostate cancer was also less than that of patients with moderately and highly differentiated prostate cancer.But there was no statistical significance int the difference(P>0.05);the proportion of patients with length<22 at clinical stage C-D was much larger than that of patients at clinical stage B(P<0.05),and as the aggravation of pathological grading,the proportion of patients with the length<22 was also remarkably increased and there was significant difference between patients with highly differentiated prostate cancer and those with poorly differentiated prostate cancer(P<0.05).Conclusions:There is correlation between the occurrence and development of prostate cancer in Han population and the polymorphism of repetitive sequence in gene CAG of androgen receptor.The less the number of repetitive sequence in CAG is,the higher the risk of prostate cancer will be and the more severe the clinical stage and pathological grading will be.
文摘To further investigate the molecular mechanism of androgen insensitivity syndromes (AIS), exons B to H of the androgen receptor (AR) gene in seven Chinese patients with Complete AlS (CAIS) were examined by the polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) analysis and direct DNA sequencing. Four distinct point mutations (Gly743Arg, Va1866Met, Arg752Gln, T2919→deletion) were identified in 4patients, and all the mutations were localized in exons E or G encoding androgen binding domain of AR. The frame-shift mutation caused by deletion of T2919 had not been reported yet so far, therefore, It was a novel mutation. Detection of the AR gene in 2 mothers showed both of them were heterozygotes carrying the same mutationsas their daughters. our study was helpful for further delineating the diversity of genetic alterations of the AR gene in patients with AlS and better understanding the relationships between structure and function of AR.
文摘The mechanism of antifertility effect of testosterone undecanoate on male rat was investigated. Eight 12-week old rats were injected with 20 mg/kg of testosterone undecanoate at bi--week intervals for 3 months. As compared to that in the 10 control rafs, the sperm density in testis rete fluid of the treatment rats declined by 7%, the motility of sperm from epididymis cauda reduced to 6%. While the testosterone level in serum increased to 255 %, the testosterone level in testis rete fluid decreased to 55%. All of these differences were significant. The androgen receptor gene expression in the testis and epididymis was suppressed in the treatment group. The decrease in output of the sperm and sperm motility of epididymis cauda may be due to the reduced testosterone production by Leydig cells and suppression of androgen receptor gene expression in testis and epididymis.
文摘2M NaCl-insoluble fraction of rat ventral prostatechromatin(residual proteins)contain proteins able tointeract specifically with androgen-receptor complex andis,therefore,a part of the acceptor complex.Amongresidual proteins,a 97 KDa protein has been found whichbinds signifieantly to a genomic fragment containingan androgen-regulated gene coding for a 22 KDa protein.The biological significance of this binding in androgenaction need to be further studied. A mini-plasmid clone containing 22 KDa proteincoding sequence was cloned into Charon 4A genomiclibrary from which a 5.7 Kb genomic fragment wasisolated,identified by hybridization with a 5’ and a 3’cDNA probes,and shown to contain the 5’ flankingsequence.Restriction enzyme treatment of this fragmentyielded a 4.7 Kb restriction fragment representingthe 5’ upstream region and a 1.0 Kb containing part ofthe coding sequence.Deletion studies indicated that the97 KDa protein bound only to a subclone of about 300 bpsegment.Furthermore,gel shifting experiment supportedits DNA-prptein binding.
文摘Aim:To investigate the involvement of the prostate androgen-regulated(PAR)gene in the androgen receptor(AR) signaling pathway and the malignant phenotype of androgen-independent prostate cancer(PCa)cells.Methods:The difference in PAR expression between LNCaP and PC3 cells was detected by reverse transcription-polymerase chain reaction(RT-PCR).Androgen and anti-androgen effects on PAR expression were evaluated by RT-PCR in LNCaP,PC3 cells and PC3 cells stably transfected with vector containing wild-type AR.To determine the importance of PAR in the malignant proliferation of androgen-independent PCa cells,we used small interfering RNA(siRNA)transfection to knock down the expression of the gene in PC3 cells.The changes in the malignant phenotype of PCa cells after transfection were analyzed by cell count,colony formation in soft agar and flow cytometry.Results:PAR expression was 3-fold higher in PC3 cells than that in LNCaP cells.Dihydrotestosterone(DHT)regulated PAR mRNA expression in LNCaP cells and the effect was inhibited by the AR antagonist,flutamide.By contrast,DHT did not affect PAR expression in PC3 cells.The reintroduction of AR into PC3 cells by stable transfection restored the androgen effect on PAR upregulation. After the knockdown of the PAR gene by siRNA,PC3 cells exhibited a reversal of the malignant phenotype.Conclusion: Because of the possibility that PAR is downstream from the AR,and because of its contribution to malignant proliferation in androgen-independent PCa cells,the gene could be a potential therapeutic target for androgen-independent PCa with AR signaling pathway alteration.(Asian J Andro12006 Jul;8:455-462)