The spectrum of phenotypes associated with mutations in steroidogenic factor 1 (SF-1, NR5A1, Ad4BP) includes severe penoscrotal hypospadias in 46,XY males without adrenal insufficiency
The spectrum of phenotypes associated with mutations in steroidogenic factor 1 (SF-1, NR5A1, Ad4BP) includes severe penoscrotal hypospadias in 46,XY males without adrenal insufficiency
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DOI：
10.1530/eje-09-0067
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发表时间：
2009-08-01
影响因子：
5.8
通讯作者：
Achermann, John C.
中科院分区：
文献类型：
--
作者：
Koehler, Birgit;Lin, Lin;Achermann, John C.
目的：尿道下裂是一种常见的先天性尿道下裂。先天性异常，但大多数病例都是潜在的，原因是没有找到。类固醇生成因子I（SF-1。NR5A1。Ad4BP）是人类性发育的关键调节因子，并且在46，XY性发育障碍（DSD）中报道了越来越多的SF-1（NR5A1）突变。我们假设NR5A1突变可以在男性尿道下裂患者中发现。设计和方法：对来自德国DSD网络的60例不同程度尿道下裂患者进行NR5A1突变分析。这三个人代表了研究范围中最严重的一端，因为他们表现为阴茎阴囊尿道下裂、阴茎的可变雄激素化和隐睾（20例（15%）具有这种表型的病例中的Till-CC）。所有3例患者的睾酮水平均较低，2例患者的睾酮B/抗苗勒管激素（AMH）水平较低。2例患者有明确的男性性别分配。第三例患者性别重新分配为男性。2例患者携带杂合无义突变（p.Q107X/WT. p.E11X/WT）。1例患者在内含子2（c.103 - 3A/WT）中存在杂合剪接位点突变，预计会破坏主要的DNA结合基序。无义突变体的功能研究表明受损的SF-1响应启动子（Cyp11a）的转录激活。迄今结论：SF-1（NR5A1）基因突变可能存在于46，XY的重度尿道下裂患者中。尤其是隐睾症患者存在低睾酮或低抗苗勒氏剂B/AMH水平。SF-1基因突变在轻度的特发性尿道下裂中并不常见。
Objective: Hypospadias is a frequent. congenital anomaly but ill most Cases all underlying, Cause is not found. Steroidogenic factor I (SF-1. NR5A1. Ad4BP) is a key regulator of human Sex development and an increasing number of SF-1 (NR5A1) mutations are reported in 46,XY disorders of sex development (DSD). We hypothesized that NR5A1 mutations Could be identified in boys with hypospadias.Design and methods: Mutational analysis of NR5A1 in 60 individuals With varying degrees of hypospadias from the German DSD network.Results: Heterozygous NR5A1 mutations were found in three Out of 60 cases. These three individuals represented the most severe end of the spectrum studied as they presented with penoscrotal hypospadias, variable androgenization of the phallus and undescended testes (till-CC out of 20 cases (15%) with this phenotype). Testosterone was low in all three patients and inhibin B/anti-Mullerian hormone (AMH) were low in two patients. Two patients had a clear male gender assignment. Gender re-assignment to male occurred in the third case. Two patients harbored heterozygous nonsense mutations (p.Q107X/WT.p.E11X/WT). One patient had a heterozygous splice site mutation in intron 2 (c.103-3A/WT) predicted to disrupt the main DNA-binding Motif. Functional studies of the nonsense mutants showed impaired transcriptional activation of an SF-1-responsive promoter (Cyp11a). To date. adrenal insufficiency has not occurred in any of the patients.Conclusions: SF-1 (NR5A1) mutations should be Considered in 46,XY individuals with Severe (penoscrotal) hypospadias. especially if undescended testes. low testosterone, or low inhibin B/AMH levels are present. SF-1 mutations in milder forms of idiopathic hypospadias are unlikely to be common.