46，XY女性性逆转患者的SF-1基因分析研究
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摘要
背景与目的：
性逆转综合征是一种由于性别决定和分化异常导致的两性畸形,其主要特征是患者的核型与表型相反,分为46,XX男性和46,XY女性两型。目前对于性腺分化的分子机制、信号途径了解还很不够,对人类性腺分化的遗传调控的了解,也是问题远多于答案。通过遗传分析性逆转患者来研究胚胎性腺发育和分化等相关基因是一条比较便捷的通道。SF-1(又名NR5A1, FTZ-F1, Ad4BP)是核受体家族的一员,调节多数性腺发育和生殖基因,是和下丘脑-脑垂体-生成类固醇轴相关的关键转录调节基因。SF-1基因敲除老鼠展示了完全的肾上腺和性腺发育不全。随着在XY性腺发育不全和原发卵巢功能不全中不断发现的SF-1基因突变充分说明了SF-1在肾上腺和性腺功能的操控和维护中起到了关键的作用。因而SF-1是引起合并或无肾上腺衰竭的46,XY性腺发育障碍的原因。本实验通过测序分析XY女性性逆转患者的SF-1基因突变情况来进一步认证SF-1与XY女性性逆转的相关性。
方法：
收集2007年1月至2009年9月到我院就诊的女性临床表型但染色体核型却为46,XY的性逆转患者的EDTA抗凝全血和血清样本6例。首先检测血清性激素系列和皮质醇,然后抽提DNA,再根据SF-1的2-7外显子的序列设计的引物进行聚合酶链反应(PCR)反应。最后对PCR产物直接测序分析以及对PCR产物检出的突变进行连接质粒后再测序和限制性内切酶分析的验证突变分析。针对未见报道的新突变,筛查110名表型和核型一致的无关个体,排除多态的可能。
结果：
在样本4的Exon4中检出了一个的新的突变(p.V128A)和一个报道过的多态突变(p.G146A).样本1中也检出了一个和样本4相同的多态突变。p.V128A在110例正常对照人群中未发现相同的突变,P.G146A在正常对照人群中检出了37.3%的突变率。6例样本中除了样本2的皮质醇低于正常值提示可能合并有肾上腺功能不全外,其余样本肾上腺功能均正常。
结论：
我们在46,XY性逆转中又检出了一个新的SF-1的基因突变,低睾酮患者中的突变检出率为25%,由此可以推断SF-1的基因突变和性逆转的发生是相关的。
Background and Objective:
sex reversal syndrome characterised by discrepancy in karyotype and Phenotype is a hermaphrodism due to abnormity of Sex Determination and differentiation. Sex reversal syndrome is divided into 46,XX male and 46,XY female. Currently understanding of the molecular mechanism and signaling pathways for gonadal differentiation, and the genetic regulation of sexual differentiation of human are more problems than answers. Genetic analysis of genes involved in embryonic gonadal development and differentiation in sex reversal is a relatively convenient access. SF-1, also named NR5A1, FTZ-F1, Ad4BP, is an orphan nuclear receptor that regulates the transcription of many genes involved in sexual developmental and reproduction. It is a key transcription regulation gene involved in the hypothalamic- pituitary-steroidogenic axis. SF-1 knock-out mouse models exhibit complete adrenal and gonadal agenesis. More recently, identification of novel SF-1 mutations responsible for isolated 46,XY gonadal dysgenesis or 46,XX primary ovarian insufficiency, underscores its central role in the control and maintenance of adrenal and reproductive functions. Thus experimental evidence from studies suggests that mutation of NR5A1 causes 46,XY disorders of sex development, with or without adrenal failure. Our aim was to test the hypothesis that mutations in SF-1 cause 46,XY sex reversal.
Methods:
Collect the whole blood and serum of 6 cases of 46,XY female sex reversal patient to our hospital from January 2007 to 2009 September. Detecting serum sex hormones and cortisol was carried out at the first time.Genomic DNA was then extracted from peripheral blood leukocytes and exons 2-7 of the gene encoding SF-1 (NR5A1) were PCR-amplified. And direct sequencing was carried out to detect the mutation.Plasmid transfection and PCR-restriction enzyme digestion was applied to detect the results of DNA sequencing.Novel mutation was screened in 110 normal individuals who is unrelated persons with normal phenotypes to exclude the possibility of polymorphism.
Results:
A novel mutation of p.V128A and a polymorphic mutation of p.G146A in Exon4 in patient 4 was identified. We also detected the polymorphic mutation of p.G146A in the patient 1.We did not observe the novel mutation in 110 normal individuals. p.G146A in normal individuals was detected in 37.3% mutation rate.All patients were without adrenal insufficiency except Patient 2 whose cortisol is lower than normal value.
Conclusion:
Thus, We identified a novel SF-1 mutation in 46,XY sex reversal.We showed the 25% prevalence of SF-1 mutations in 46,XY sex reversal with low serum testosterone concentration. So it imply SF-1 mutations is a relatively frequent cause of 46,XY DSD in humans.
性逆转综合征是一种由于性别决定和分化异常导致的两性畸形,其主要特征是患者的核型与表型相反,分为46,XX男性和46,XY女性两型。目前对于性腺分化的分子机制、信号途径了解还很不够,对人类性腺分化的遗传调控的了解,也是问题远多于答案。通过遗传分析性逆转患者来研究胚胎性腺发育和分化等相关基因是一条比较便捷的通道。SF-1(又名NR5A1, FTZ-F1, Ad4BP)是核受体家族的一员,调节多数性腺发育和生殖基因,是和下丘脑-脑垂体-生成类固醇轴相关的关键转录调节基因。SF-1基因敲除老鼠展示了完全的肾上腺和性腺发育不全。随着在XY性腺发育不全和原发卵巢功能不全中不断发现的SF-1基因突变充分说明了SF-1在肾上腺和性腺功能的操控和维护中起到了关键的作用。因而SF-1是引起合并或无肾上腺衰竭的46,XY性腺发育障碍的原因。本实验通过测序分析XY女性性逆转患者的SF-1基因突变情况来进一步认证SF-1与XY女性性逆转的相关性。
方法：
收集2007年1月至2009年9月到我院就诊的女性临床表型但染色体核型却为46,XY的性逆转患者的EDTA抗凝全血和血清样本6例。首先检测血清性激素系列和皮质醇,然后抽提DNA,再根据SF-1的2-7外显子的序列设计的引物进行聚合酶链反应(PCR)反应。最后对PCR产物直接测序分析以及对PCR产物检出的突变进行连接质粒后再测序和限制性内切酶分析的验证突变分析。针对未见报道的新突变,筛查110名表型和核型一致的无关个体,排除多态的可能。
结果：
在样本4的Exon4中检出了一个的新的突变(p.V128A)和一个报道过的多态突变(p.G146A).样本1中也检出了一个和样本4相同的多态突变。p.V128A在110例正常对照人群中未发现相同的突变,P.G146A在正常对照人群中检出了37.3%的突变率。6例样本中除了样本2的皮质醇低于正常值提示可能合并有肾上腺功能不全外,其余样本肾上腺功能均正常。
结论：
我们在46,XY性逆转中又检出了一个新的SF-1的基因突变,低睾酮患者中的突变检出率为25%,由此可以推断SF-1的基因突变和性逆转的发生是相关的。
Background and Objective:
sex reversal syndrome characterised by discrepancy in karyotype and Phenotype is a hermaphrodism due to abnormity of Sex Determination and differentiation. Sex reversal syndrome is divided into 46,XX male and 46,XY female. Currently understanding of the molecular mechanism and signaling pathways for gonadal differentiation, and the genetic regulation of sexual differentiation of human are more problems than answers. Genetic analysis of genes involved in embryonic gonadal development and differentiation in sex reversal is a relatively convenient access. SF-1, also named NR5A1, FTZ-F1, Ad4BP, is an orphan nuclear receptor that regulates the transcription of many genes involved in sexual developmental and reproduction. It is a key transcription regulation gene involved in the hypothalamic- pituitary-steroidogenic axis. SF-1 knock-out mouse models exhibit complete adrenal and gonadal agenesis. More recently, identification of novel SF-1 mutations responsible for isolated 46,XY gonadal dysgenesis or 46,XX primary ovarian insufficiency, underscores its central role in the control and maintenance of adrenal and reproductive functions. Thus experimental evidence from studies suggests that mutation of NR5A1 causes 46,XY disorders of sex development, with or without adrenal failure. Our aim was to test the hypothesis that mutations in SF-1 cause 46,XY sex reversal.
Methods:
Collect the whole blood and serum of 6 cases of 46,XY female sex reversal patient to our hospital from January 2007 to 2009 September. Detecting serum sex hormones and cortisol was carried out at the first time.Genomic DNA was then extracted from peripheral blood leukocytes and exons 2-7 of the gene encoding SF-1 (NR5A1) were PCR-amplified. And direct sequencing was carried out to detect the mutation.Plasmid transfection and PCR-restriction enzyme digestion was applied to detect the results of DNA sequencing.Novel mutation was screened in 110 normal individuals who is unrelated persons with normal phenotypes to exclude the possibility of polymorphism.
Results:
A novel mutation of p.V128A and a polymorphic mutation of p.G146A in Exon4 in patient 4 was identified. We also detected the polymorphic mutation of p.G146A in the patient 1.We did not observe the novel mutation in 110 normal individuals. p.G146A in normal individuals was detected in 37.3% mutation rate.All patients were without adrenal insufficiency except Patient 2 whose cortisol is lower than normal value.
Conclusion:
Thus, We identified a novel SF-1 mutation in 46,XY sex reversal.We showed the 25% prevalence of SF-1 mutations in 46,XY sex reversal with low serum testosterone concentration. So it imply SF-1 mutations is a relatively frequent cause of 46,XY DSD in humans.
引文
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