Five novel mutations in steroidogenic factor 1 (SF1, NR5A1) in 46,XY patients with severe underandrogenization but without adrenal insufficiency.
Five novel mutations in steroidogenic factor 1 (SF1, NR5A1) in 46,XY patients with severe underandrogenization but without adrenal insufficiency.
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46例患有严重不给源性的XY患者，但没有肾上腺功能不全。
DOI：
10.1002/humu.20588
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发表时间：
2008-01
期刊：
影响因子：
3.9
通讯作者：
Achermann, John C.
中科院分区：
文献类型：
--
作者：
Koehler, Birgit;Lin, Lin;Ferraz-de-souza, Bruno;Wieacker, Peter;Heidemann, Peter;Schroeder, Vanessa;Biebermann, Heike;Schnabel, Dirk;Grueters, Annette;Achermann, John C.
关键词：
类固醇生成因子1(SF1，NR5A1)是一种核受体，调节多个基因，涉及肾上腺和性腺发育、类固醇激素生成和生殖轴。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女性患者中发现。然而，最近的病例报道表明，在46，XY部分性腺发育不全和雄激素不足但肾上腺功能正常的患者中也可能发现SF1杂合突变。我们分析了来自德国性发育障碍网络的27例46，XY性发育障碍(DSD)患者的SF1(NR5A1)编码基因。27例中有5例(18.5%)存在SF1杂合性突变。4例SF1基因突变的患者表现出相似的表型，表现为轻度性腺发育不全、严重的雄激素不足和缺乏苗勒氏结构。在这些患者中，两名患者在SF1的DNA结合区(p.C33S，p.R84H)存在错义突变，一名患者存在无义突变(p.Y138X)，一名患者存在移码突变(c.1277dupT)，预计会破坏RNA的稳定性或蛋白质功能。另1例患者([c.424_427dupCCCA]+[p.G146A])表现出更明显的严重性腺发育不全、女性外生殖器正常和缪勒结构。对错义突变体(p.C33S，p.R84H)和一个无义突变体(p.Y138X)的功能研究表明，SF1反应靶基因的转录激活受损。到目前为止，没有一名患者出现肾上腺功能不全。因此，SF1突变是人类46，XY DSD的一种相对常见的原因。
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.
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影响因子：
5.8
作者：
Correa, RV;Domenice, S;Mendonca, BB
通讯作者：
Mendonca, BB
DOI：
10.1016/j.bbrc.2003.10.096
发表时间：
2003-11-28
影响因子：
3.1
作者：
Fan, WQ;Yanase, T;Nawata, H
通讯作者：
Nawata, H
影响因子：
5.8
作者：
Hasegawa, T;Fukami, M;Ogata, T
通讯作者：
Ogata, T
影响因子：
4.6
作者：
Lin, CL;Chiu, WY;Lee, CF
通讯作者：
Lee, CF
影响因子：
4.8
作者：
Majdic, G;Young, M;Parker, KL
通讯作者：
Parker, KL