尿道下裂发病相关基因突变的研究和包皮内板全厚皮片（阴囊中厚皮片）游离移植耦合包皮岛状皮瓣治疗各型尿道下裂
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，是一种迄今为止原因不明的性分化异常，其发病率约为3‰，并且在许多国家中尿道下裂的发病率具有增加的趋势。
大多数尿道下裂患者的发病原因仍不清楚，有关尿道下裂病因学的研究近年来得到了很大进展，但影响位置和影响方式尚未明确。综观目前的研究，主要有以下四方面的探索：遗传因素、内分泌因素、环境因素和其它因素。
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。SRY基因是决定男性性分化的起点，它可以激活一系列的基因调控级联反应，对男性性分化的启动和性发育的正常进行有重要的影响。SOX9可能是SRY的一个下游基因，起着承前启后的作用。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。WT1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，而且有可能参与后来的发育调控。MID1在中缝结构的发育中起重要作用。SRY、SOX9、SRD5A2、AR、WT1、MID1这6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，所以挑选它们作为尿道下裂发病相关基因的首批突变筛查对象。
我们以95例患者的基因组DNA作为模板，扩增了以上6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，如此大样本、多基因的系列筛查尿道下裂发病相关基因的突变，尚未见报道。
我们在24名患者中发现了18个突变位点，在6名患者中发现染色体异常，二者占总患者人数的31.6％，10个突变位点未曾报道过。筛查的6个基因的突变结果如下：(1)SRY基因：未发现突变，但发现4例SRY阴性患者。其中，3例染色体核型为46，XX，临床检验证实一例为女性肾上腺皮质增生症；一例为真两性畸形；一例为阴囊型尿道下裂，另1例SRY阴性患者染色体核型不详，为阴茎型尿道下裂。我们还发现两例患者染色体核型异常，分别为45，XO(18％)／46，XY(82％)和46，X dic(Y)／45，XO，均为阴囊型尿道下裂。(2)SOX9基因：未发现突变。(3)SRD5A2基因：在14个病人中发现了8种突变，占总病人数的14.7％，表明约1／10的尿道下裂患者存在不同程度的类固醇5α—还原酶Ⅱ基因结构异常；我们筛查出的突变，包含5种错
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 incidence of hypospadias is 3‰ and the incidence is increasing in many countries.
The etiology of hypospaias is still unclear, although great progress has been made. At present, there are four factors that maybe affect the onset of hypospadias, including genetic factor, endocrine, environment and others.
Normal sex differentiation of male is a consecutive, ordered and inter-related process, requiring equilibrium of many gene interactions. SRY gene 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. 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. WT1 not only regulates cascade reaction of sex differentiation through interacting with SRY, MIS, SF1 and DAX1 but also participates i n the posterior developmental phase. MID1 is essential for the development of midline structure. SRY, WTl, S0X9, SRD5A2 AR and MID1 are all important in differentiation and development of male genital system and act in different stages. Therefore, the six genes were selected as first choice for hypospadias genetic analysis.
All exons of above six genes were amplified from the genomic DNA of 95 cases. It is the first t ime t hat t he s erial genes w hich are related t o h ypospadias a re detected i n s o many patients. Mutations were detected by directly sequencing of PCR products. SRY gene was tested using multiplex PCR.
18 mutations were detected from 24 cases, and the karyotypes were abnormal in 6 cases. The cases for these two types accounted for 31.6% of all cases. 10 mutations are novel. While in contol group, 2 mutations were detected from 5 cases. The difference is significant b etween c ontrol group and test group. The results of tested six genes are as follows. (1) SRY: no mutation was detected. SRY was negative in 4 cases, within which 3
大多数尿道下裂患者的发病原因仍不清楚，有关尿道下裂病因学的研究近年来得到了很大进展，但影响位置和影响方式尚未明确。综观目前的研究，主要有以下四方面的探索：遗传因素、内分泌因素、环境因素和其它因素。
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。SRY基因是决定男性性分化的起点，它可以激活一系列的基因调控级联反应，对男性性分化的启动和性发育的正常进行有重要的影响。SOX9可能是SRY的一个下游基因，起着承前启后的作用。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。WT1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，而且有可能参与后来的发育调控。MID1在中缝结构的发育中起重要作用。SRY、SOX9、SRD5A2、AR、WT1、MID1这6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，所以挑选它们作为尿道下裂发病相关基因的首批突变筛查对象。
我们以95例患者的基因组DNA作为模板，扩增了以上6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，如此大样本、多基因的系列筛查尿道下裂发病相关基因的突变，尚未见报道。
我们在24名患者中发现了18个突变位点，在6名患者中发现染色体异常，二者占总患者人数的31.6％，10个突变位点未曾报道过。筛查的6个基因的突变结果如下：(1)SRY基因：未发现突变，但发现4例SRY阴性患者。其中，3例染色体核型为46，XX，临床检验证实一例为女性肾上腺皮质增生症；一例为真两性畸形；一例为阴囊型尿道下裂，另1例SRY阴性患者染色体核型不详，为阴茎型尿道下裂。我们还发现两例患者染色体核型异常，分别为45，XO(18％)／46，XY(82％)和46，X dic(Y)／45，XO，均为阴囊型尿道下裂。(2)SOX9基因：未发现突变。(3)SRD5A2基因：在14个病人中发现了8种突变，占总病人数的14.7％，表明约1／10的尿道下裂患者存在不同程度的类固醇5α—还原酶Ⅱ基因结构异常；我们筛查出的突变，包含5种错
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 incidence of hypospadias is 3‰ and the incidence is increasing in many countries.
The etiology of hypospaias is still unclear, although great progress has been made. At present, there are four factors that maybe affect the onset of hypospadias, including genetic factor, endocrine, environment and others.
Normal sex differentiation of male is a consecutive, ordered and inter-related process, requiring equilibrium of many gene interactions. SRY gene 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. 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. WT1 not only regulates cascade reaction of sex differentiation through interacting with SRY, MIS, SF1 and DAX1 but also participates i n the posterior developmental phase. MID1 is essential for the development of midline structure. SRY, WTl, S0X9, SRD5A2 AR and MID1 are all important in differentiation and development of male genital system and act in different stages. Therefore, the six genes were selected as first choice for hypospadias genetic analysis.
All exons of above six genes were amplified from the genomic DNA of 95 cases. It is the first t ime t hat t he s erial genes w hich are related t o h ypospadias a re detected i n s o many patients. Mutations were detected by directly sequencing of PCR products. SRY gene was tested using multiplex PCR.
18 mutations were detected from 24 cases, and the karyotypes were abnormal in 6 cases. The cases for these two types accounted for 31.6% of all cases. 10 mutations are novel. While in contol group, 2 mutations were detected from 5 cases. The difference is significant b etween c ontrol group and test group. The results of tested six genes are as follows. (1) SRY: no mutation was detected. SRY was negative in 4 cases, within which 3
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