Köhler Birgit, Lin Lin, Ferraz-de-Souza Bruno, Wieacker Peter, Heidemann Peter, Schröder Vanessa, Biebermann Heike, Schnabel Dirk, Grüters Annette, Achermann John C
Department of Pediatric Endocrinology, University Children's Hospital, Charité, Humboldt University, Berlin, Germany.
Hum Mutat. 2008 Jan;29(1):59-64. doi: 10.1002/humu.20588.
Steroidogenic factor 1 (SF1, NR5A1) is a nuclear receptor that regulates multiple genes involved in adrenal and gonadal development, steroidogenesis, and the reproductive axis. Human mutations in SF1 were initially found in two 46,XY female patients with severe gonadal dysgenesis and primary adrenal failure. However, more recent case reports have suggested that heterozygous mutations in SF1 may also be found in patients with 46,XY partial gonadal dysgenesis and underandrogenization but normal adrenal function. We have analyzed the gene encoding SF1 (NR5A1) in a cohort of 27 patients with 46,XY disorders of sex development (DSD) from the German network of DSD. Heterozygous SF1 mutations were found in 5 out of 27 (18.5%) of cases. Four patients with SF1 mutations presented with the similar phenotype of mild gonadal dysgenesis, severe underandrogenization, and absent Müllerian structures. Of these, two patients harbored missense mutations within the DNA-binding region of SF1 (p.C33S, p.R84H), one patient had a nonsense mutation (p.Y138X) and one patient had a frameshift mutation (c.1277dupT) predicted to disrupt RNA stability or protein function. One additional patient ([c.424_427dupCCCA]+[p.G146A]) displayed a more marked phenotype of severe gonadal dysgenesis, normal female external genitalia, and Müllerian structures. Functional studies of the missense mutants (p.C33S, p.R84H) and of one nonsense mutant (p.Y138X) revealed impaired transcriptional activation of SF1-responsive target genes. To date, adrenal insufficiency has not occurred in any of the patients. Thus, SF1 mutations are a relatively frequent cause of 46,XY DSD in humans.
类固醇生成因子1（SF1，NR5A1）是一种核受体，可调节参与肾上腺和性腺发育、类固醇生成及生殖轴的多个基因。人类SF1基因突变最初在两名患有严重性腺发育不全和原发性肾上腺功能衰竭的46,XY女性患者中被发现。然而，最近的病例报告表明，在患有46,XY部分性腺发育不全和雄激素化不足但肾上腺功能正常的患者中也可能发现SF1的杂合突变。我们分析了来自德国性发育障碍（DSD）网络的27例46,XY性发育障碍（DSD）患者队列中编码SF1（NR5A1）的基因。27例病例中有5例（18.5%）发现了杂合性SF1突变。4例携带SF1突变的患者表现出相似的表型，即轻度性腺发育不全、严重雄激素化不足和苗勒氏结构缺失。其中，2例患者在SF1的DNA结合区域内存在错义突变（p.C33S，p.R84H），1例患者存在无义突变（p.Y138X），1例患者存在移码突变（c.1277dupT），预计会破坏RNA稳定性或蛋白质功能。另外1例患者（[c.424_427dupCCCA]+[p.G146A]）表现出更明显的表型，即严重性腺发育不全、正常女性外生殖器和苗勒氏结构。对这些错义突变体（p.C33S，p.R84H）和一个无义突变体（p.Y138X）的功能研究表明，SF1反应性靶基因的转录激活受损。迄今为止，所有患者均未出现肾上腺功能不全。因此，SF1突变是人类46,XY DSD相对常见的原因。
