新发睾丸决定基因SRY突变导致46,XY性发育异常三例

Three cases of novel SRY mutations causing 46,XY disorder of sex development

目的在46,XY性发育异常疾病(46,XY DSD)患者中进行SRY突变检测,分析其发生频率,并总结检出SRY突变患者的临床特点。方法纳入2009-2014年在北京协和医院内分泌科就诊的46,XY DSD患者63例,收集详细临床资料,提取外周血基因组DNA,PCR特异性扩增SRY并进行Sanger测序,通过与在线数据库比对确定突变,分析临床特点。结果 63例患者中共有三例检出SRY的3种新突变(约5%)。这三例患者社会性别均为女性,染色体核型为46,XY,有阴道和子宫结构,性激素符合高促性腺激素性性腺功能减退症。3种突变分别为:Pro131His、R76C和L35Afs*25。前2种错义突变位点位于HMG box核定位信号区,累及高度保守氨基酸,后1种为移码突变导致HMG box缺失,均严重破坏了SRY蛋白的重要功能结构域。结论该研究发现的3种SRY新突变是导致46,XY DSD的病因,SRY突变的检出率约为5%;对于46,XY DSD患者,建议均行SRY检测以明确病因。

Objective To detect SRY mutation in 46,XY disorder of sex development（ 46,XY DSD）,analyze SRY mutation frequency,and to define the clinical features of the patients with the mutation. Methods A total of sixtythree 46,XY DSD patients admitted to department of endocrinology of Peking Union Medical College Hospital from2009 to 2014 were enrolled and detailed clinical data were collected. Genomic DNA was extracted from peripheral blood,and SRY was amplified and sequenced. The mutation was identified by comparing with the online database,and the clinical features were analyzed. Results Three novel mutations of SRY gene were detected in 3 of 63 patients（ 5%）. The 3 patients＇ social genders were all female and their karyotypes are 46,XY. Vaginal and uterine structures were present. Sex hormone profiles were consistent with hypergonadotropic hypogonadism. The 3 novelmutations were Pro131 His,R76 C and L35 Afs＊25. The former two were mutations in the nuclear localization signal regions of HMG box and highly-conservative amino acids were affected. The latter one was a frameshift mutation resulting in deletion of the entire HMG box. All these were presumably affecting the functional domain of SRY protein severely. Conclusions This study identified three novel mutations of SRY gene causing 46,XY DSD. The detection rate of SRY mutation was about 5%. It is recommended that SRY testing be performed to identify the etiology of the disease.