【作者】 李远伟；

【导师】 赵晓昆；

【作者基本信息】 中南大学 ， 外科学， 2006， 博士

【摘要】 尿道下裂主要表现为异位的尿道外口，在男性新生儿中其发病率约为1／250～300，它是男性泌尿生殖系统最常见先天性畸形之一。近30年来尿道下裂的发病率呈逐年升高趋势，大部分是散发的、无遗传和家族史。既往研究显示尿道下裂存在家族性单基因遗传现象，或伴发于其它的遗传疾病综合症，同时也有研究发现环境因素与尿道下裂有关，目前认为尿道下裂是遗传和环境因素综合作用的结果。 胎儿尿道发育有赖于足量的雄性激素，它包括睾酮和双氢睾酮，睾酮在由SRD5A2基因编码的Ⅱ型5α-还原酶的作用下转化成活性更高的双氢睾酮。研究证明Ⅱ型5α-还原酶的功能异常、SRD5A2基因突变和尿道下裂的发生有密切关系，至今已发现约40种突变类型，大部分表现为误义突变和无义突变。以往对该基因的研究主要集中在家族性和伴发于其它遗传疾病综合症的尿道下裂，对散发的单纯性尿道下裂研究较少。 ATF3是碱性亮氨酸拉链区(bZIP)家族中ATF／CREB转录因子亚家族的成员之一。研究发现ATF3通过复杂的机制调节其靶基因的表达，它与内环境稳定、伤口愈合、细胞粘附、肿瘤细胞浸润和信号转导通路有关。2003年，Wang等采用微阵列技术发现ATF3是尿道下裂相关基因之一，提示ATF3基因除了对应激产生保护性反应外，可能与尿道下裂发生过程中的应激应答有关。进一步研究ATF3和散发的单纯性尿道下裂的关系，有可能揭示ATF3在其发病中的作用机制。 家族性尿道下裂约占7％，其余的大部分为散发的单纯性尿道下裂。更多还原

【Abstract】 Hypospadias is a malformation characterized by the urethra opening on the underside of the penis. The reported incidence of hypospadias is approximately l/250~l/300 live male births, making hypospadias one of the most common congenital malformations in children. Some research has documented that the incidence of this anomaly has been increasing during the last three decades, and most hypospadias are sporadic, without inheritance or family recurrence. Evidence for genetic factors in hypospadias come from the observation of families with monogenic inheritance and the feature of hypospadias in several genetic syndromes. Moreover, environmental factors may also contribute to the pathogenesis of hypospadias. Taken together hypospadias is a complex disorder caused by the combined influence of genetic and environmental factors.Normal male sex differentiation relies on the effect of androgen. The conversion of testosterone (T) to dihydrotestosterone (DHT), required for the full masculinization of the external genitalia and prostate in the male foetus, is catalysed by the 5a-reductase-2 enzyme, which is encoded by the SRD5A2 gene located on the short arm of chromosome 2. Extensive mutation screening in hypospadias have revealed disease associated sequence alterations predominantly in the steroid 5-alpha reductase (SRD5A2) gene and more than 40 different mutations have been reported so far in the SRD5A2 gene, most are missense or nonsense mutations. Previous works were focus on familial hypospadias or other genetic syndromes, and the association of SRD5A2 mutations with isolated hypospadias was rarely studied.Activating transcription factor 3 (ATF3) is a member of the ATF/CREB更多还原