Mutations in NR5A1 associated with ovarian insufficiency.
Mutations in NR5A1 associated with ovarian insufficiency.
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DOI：
10.1056/nejmoa0806228
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发表时间：
2009-03-19
期刊：
影响因子：
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通讯作者：
Bashamboo A
中科院分区：
文献类型：
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作者：
Lourenço D;Brauner R;Lin L;De Perdigo A;Weryha G;Muresan M;Boudjenah R;Guerra-Junior G;Maciel-Guerra AT;Achermann JC;McElreavey K;Bashamboo A
非综合征性卵巢功能不全的遗传原因在很大程度上尚不清楚。核受体 NR5A1（也称为类固醇生成因子 1）是参与下丘脑-垂体-类固醇生成轴的基因的关键转录调节因子。 NR5A1 突变会导致 46,XY 性发育障碍，伴有或不伴有肾上腺衰竭，但来自小鼠研究的越来越多的实验证据表明，该因素在卵巢发育和功能中也发挥着关键作用。为了检验 NR5A1 突变导致卵巢发育和功能障碍的假设，我们对具有 46,XY 性发育障碍和 46,XX 原发性卵巢功能不全病史的 4 个家庭以及 25 名散发性卵巢功能不全受试者的 NR5A1 进行了测序。受影响的受试者均未出现肾上腺功能不全的临床症状。这四个家庭的成员以及 25 名孤立性卵巢功能不全受试者中的 2 名均携带 NR5A1 基因突变。检测到框内缺失、移码和错义突变。功能研究表明这些突变严重损害了 NR5A1 反式激活活性。突变与一系列卵巢异常相关，包括 46,XX 性腺发育不全和 46,XX 原发性卵巢功能不全。我们没有在 700 多个对照等位基因中观察到这些突变。 NR5A1 突变与 46,XX 原发性卵巢功能不全和 46,XY 性发育障碍有关。
The genetic causes of nonsyndromic ovarian insufficiency are largely unknown. A nuclear receptor, NR5A1 (also called steroidogenic factor 1), is a key transcriptional regulator of genes involved in the hypothalamic–pituitary–steroidogenic axis. Mutation of NR5A1 causes 46,XY disorders of sex development, with or without adrenal failure, but growing experimental evidence from studies in mice suggests a key role for this factor in ovarian development and function as well. To test the hypothesis that mutations in NR5A1 cause disorders of ovarian development and function, we sequenced NR5A1 in four families with histories of both 46,XY disorders of sex development and 46,XX primary ovarian insufficiency and in 25 subjects with sporadic ovarian insufficiency. None of the affected subjects had clinical signs of adrenal insufficiency. Members of each of the four families and 2 of the 25 subjects with isolated ovarian insufficiency carried mutations in the NR5A1 gene. In-frame deletions and frameshift and missense mutations were detected. Functional studies indicated that these mutations substantially impaired NR5A1 transactivational activity. Mutations were associated with a range of ovarian anomalies, including 46,XX gonadal dysgenesis and 46,XX primary ovarian insufficiency. We did not observe these mutations in more than 700 control alleles. NR5A1 mutations are associated with 46,XX primary ovarian insufficiency and 46,XY disorders of sex development.