尿道下裂相关基因的突变研究
摘要
尿道下裂是男性泌尿生殖系统最常见的先天性畸形之一，是一种原因不明的性别分化异常，主要表现为尿道外口异位，阴茎弯曲畸形，阴茎背侧包皮堆积等。一般报道其发病率在0.4‰0-8.2‰之间，并且在许多国家中尿道下裂的发病率具有增加的趋势，重型尿道下裂所占的比例也在逐渐增多。
大多数尿道下裂患者是散发的，但也有许多研究表明该病的发病有家族性群集倾向，而且先证者男性亲属的发病率明显高于普通人群，表明遗传因素在尿道下裂的发生中占重要的地位。目前，普遍认为尿道下裂是一种通过多基因遗传的疾病。
正常男性的性别分化是一个连续、有序和相互关联的过程，需要多种基因间的精确剂量平衡和相互作用。位于Y染色体短臂的SRY基因是决定男性性分化的起点，它可以激活一系列的分子级联反应，对男性性分化的启动和性发育的正常进行有重要的影响。在分化的早期阶段，除SRY外还需要许多因子的参与，SOX9与WT1基因就是其中两个重要的成员。SOX9可能是SRY的一个下游基因，起着承前启后的作用。WT1不但在早期发育中通过与SRY、MIS、SF1和DAX1等的相互作用来调节性分化的级联过程，而且有可能也参与了后来的发育阶段。在男性表型性别确定阶段，双氢睾酮是促使胚胎期男性外生殖器、尿道和前列腺发育的主要激素，而双氢睾酮是睾丸分泌的睾酮在Ⅱ型类固醇5α还原酶(SRD5A2)的作用下形成的。双氢睾酮和它的前体睾酮都要是通过雄激素受体(AR)作用于它们的靶器官来发挥其生物学效应。SRY、WT1、SOX9、SRD5A2、AR这5个基因在男性生殖系统分化和发育中发挥至关重要的作用，并且侧重于不同的发育阶段，所以挑选它们作为尿道下裂相关基因的首批突变筛查对象。
以95例患者的基因组DNA作为模板，扩增了以上5个基因的全部外显子，利用PCR产物直接测序的方法来检测基因外显子的突变位点。利用双重PCR技术来检测SRY基因，对SRY阴性的患者进行了核型分析。
Hypospadias, one of the most common congenital anomalies of male urogenital system, is a disease in sexual mal-differentiation, and its etiology is unclear. The main symptoms are abnormally located urethral orifice, downward curvature penis and excess dorsal prepuce. The incidence of hypospadias is 0.4‰ - 8.2‰ and the incidence is increasing in many counties, especially for the severe hypospadias.
Most of hypospadias patients are sporadic, although tendency of familial concentration is also observed. The prevalence is significantly higher in proband's male relative than in unrelated population, indicating that genetic factor plays important roles in the occurring of hypospadias. Hypospadias is supposed to be a multiple-genetic disease.
Normal sex differentiation of male is a consecutive, ordered and inter-related process, requiring equilibrium of many gene interactions. SRY gene that is localized in phocomelic arm of Y chromosome is the initial point of male sex differentiation. SRY gene initiates a series of molecular cascade reaction which is very important for normal sex development. S0X9 and WTl are important genes in the anterior differentiation phase besides SRY. S0X9 is a downstream gene of SRY and plays pivot roles. WTl not only regulates cascade reaction of sex differentiation through interacting with SRY, MIS, SF1 and DAX1 but also participates in the posterior developmental phase. In the phase of sex determination of male phenotype, dihydrotestosterone is the key hormone responsible for the development of the male external genitalia, urethra and prostate. Dihydrotestosterone is derived from testosterone by catalysis of 5 α -steroid reductase, which is encoded by the gene SRD5A2. Testosterone and dihydrotestosterone can only be effective through binding to the androgen receptor encoded by gene AR. SRY, WTl, SOX9, SRD5A2 and AR are all important in differentiation and development of male genital system and act in different stages.
大多数尿道下裂患者是散发的，但也有许多研究表明该病的发病有家族性群集倾向，而且先证者男性亲属的发病率明显高于普通人群，表明遗传因素在尿道下裂的发生中占重要的地位。目前，普遍认为尿道下裂是一种通过多基因遗传的疾病。
正常男性的性别分化是一个连续、有序和相互关联的过程，需要多种基因间的精确剂量平衡和相互作用。位于Y染色体短臂的SRY基因是决定男性性分化的起点，它可以激活一系列的分子级联反应，对男性性分化的启动和性发育的正常进行有重要的影响。在分化的早期阶段，除SRY外还需要许多因子的参与，SOX9与WT1基因就是其中两个重要的成员。SOX9可能是SRY的一个下游基因，起着承前启后的作用。WT1不但在早期发育中通过与SRY、MIS、SF1和DAX1等的相互作用来调节性分化的级联过程，而且有可能也参与了后来的发育阶段。在男性表型性别确定阶段，双氢睾酮是促使胚胎期男性外生殖器、尿道和前列腺发育的主要激素，而双氢睾酮是睾丸分泌的睾酮在Ⅱ型类固醇5α还原酶(SRD5A2)的作用下形成的。双氢睾酮和它的前体睾酮都要是通过雄激素受体(AR)作用于它们的靶器官来发挥其生物学效应。SRY、WT1、SOX9、SRD5A2、AR这5个基因在男性生殖系统分化和发育中发挥至关重要的作用，并且侧重于不同的发育阶段，所以挑选它们作为尿道下裂相关基因的首批突变筛查对象。
以95例患者的基因组DNA作为模板，扩增了以上5个基因的全部外显子，利用PCR产物直接测序的方法来检测基因外显子的突变位点。利用双重PCR技术来检测SRY基因，对SRY阴性的患者进行了核型分析。
Hypospadias, one of the most common congenital anomalies of male urogenital system, is a disease in sexual mal-differentiation, and its etiology is unclear. The main symptoms are abnormally located urethral orifice, downward curvature penis and excess dorsal prepuce. The incidence of hypospadias is 0.4‰ - 8.2‰ and the incidence is increasing in many counties, especially for the severe hypospadias.
Most of hypospadias patients are sporadic, although tendency of familial concentration is also observed. The prevalence is significantly higher in proband's male relative than in unrelated population, indicating that genetic factor plays important roles in the occurring of hypospadias. Hypospadias is supposed to be a multiple-genetic disease.
Normal sex differentiation of male is a consecutive, ordered and inter-related process, requiring equilibrium of many gene interactions. SRY gene that is localized in phocomelic arm of Y chromosome is the initial point of male sex differentiation. SRY gene initiates a series of molecular cascade reaction which is very important for normal sex development. S0X9 and WTl are important genes in the anterior differentiation phase besides SRY. S0X9 is a downstream gene of SRY and plays pivot roles. WTl not only regulates cascade reaction of sex differentiation through interacting with SRY, MIS, SF1 and DAX1 but also participates in the posterior developmental phase. In the phase of sex determination of male phenotype, dihydrotestosterone is the key hormone responsible for the development of the male external genitalia, urethra and prostate. Dihydrotestosterone is derived from testosterone by catalysis of 5 α -steroid reductase, which is encoded by the gene SRD5A2. Testosterone and dihydrotestosterone can only be effective through binding to the androgen receptor encoded by gene AR. SRY, WTl, SOX9, SRD5A2 and AR are all important in differentiation and development of male genital system and act in different stages.
引文
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