Novel NR5A1 mutations found in Chinese patients with 46, XY disorders of sex development
Novel NR5A1 mutations found in Chinese patients with 46, XY disorders of sex development
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中国 46, XY 性发育障碍患者中发现新的 NR5A1 突变
DOI：
10.1111/cen.13831
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发表时间：
2018-11-01
影响因子：
3.2
通讯作者：
Wu, Xueyan
中科院分区：
文献类型：
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作者：
Yu, Bingqing;Liu, Zhaoxiang;Wu, Xueyan
目的分析中国46，XY性发育障碍（DSD）患者中核受体亚家族5 A组成员1（NR5A1）基因突变情况。分别进行靶向下一代和桑格测序以研究致病基因变异和验证NR5A1基因变异。使用计算机模拟工具和体外功能研究来分析罕见变体的致病性。回顾性分析7例46，XY DSD患者的临床和内分泌特点，共发现4例新的NR5A1变异和3例复发的NR5A1变异。这些变体广泛分布于几乎所有的功能域。功能研究表明，包括p.S32N、p.N44del和p.G91D在内的新突变降低了CYP11A1的反式激活，而另一个错义变体p.A168E不影响蛋白质功能。所有携带NR5A1罕见变异体的患者肾上腺功能正常，并表现出生殖缺陷。生殖器检查结果显示女性外生殖器（3例患者）、不明外生殖器（2例患者）、女性外生殖器伴阴蒂肥大（1例患者）和尿道下裂（1例患者）。所有7例患者有双侧睾丸和7例患者中的5例缺乏Mullerian structures.ConclusionsFour新的突变在NR5A1基因被确定在我们的队列与46，XY DSD，扩大频谱NR5A1基因突变。所有携带NR5A1罕见变异体的患者肾上腺功能正常，并表现出生殖缺陷。
ObjectiveTo analyze nuclear receptor subfamily 5 group A member 1 (NR5A1) gene mutations in a cohort of Chinese patients with 46, XY Disorders of Sex Development (DSD).MethodsResultsSixty 46, XY DSD patients were recruited at Peking Union Medical College Hospital. Targeted next-generation and Sanger sequencing were performed to investigate pathogenic gene variants and validate NR5A1 gene variants, respectively. In silico tools and in vitro function studies were used to analyze the pathogenicity of rare variants. The clinical and endocrinological characteristics of patients with NR5A1 variants were retrospectively analyzed.A total of four novel and three recurrent NR5A1 variants were identified in seven 46, XY DSD patients. These variants widely spread almost all the functional domains. Functional studies showed that novel mutations including p.S32N, p.N44del and p.G91D reduced transactivation of CYP11A1, while the other missense variant p.A168E did not impact protein function. All patients with NR5A1 rare variants had normal adrenal function and showed genital defects. Results of the genitalia examination showed female external genitalia (three patients), ambiguous external genitalia (two patients), female external genitalia with clitoromegaly (one patient), and hypospadias (one patient). All seven patients had bilateral testis and five of seven patients lacked Mullerian structures.ConclusionsFour novel mutations in the NR5A1 gene were identified in our cohort with 46, XY DSD, expanding the spectrum of NR5A1 gene mutations. All patients with NR5A1 rare variants had normal adrenal function and showed genital defects.