Testicular dysgenesis without adrenal insufficiency in a 46,XY patient with a heterozygous inactive mutation of steroidogenic factor-1
Testicular dysgenesis without adrenal insufficiency in a 46,XY patient with a heterozygous inactive mutation of steroidogenic factor-1
复制标题
DOI：
10.1210/jc.2004-0935
复制
发表时间：
2004-12-01
影响因子：
5.8
通讯作者：
Ogata, T
中科院分区：
文献类型：
--
作者：
Hasegawa, T;Fukami, M;Ogata, T
类固醇生成因子-1（SF-1）调节参与肾上腺和性腺发育以及多种激素（包括肾上腺和性腺类固醇、抗苗勒管激素（AMH）和促性腺激素）生物合成的多个基因。我们在一名27岁的46，XY核型的日本患者中发现了一种新的SF-1突变。对SF-1的所有7个外显子进行序列分析，揭示了在外显子2（18 delC）处的杂合单碱基对缺失，预测其导致在第6个密码子处的移码和在第74个密码子处的最终终止。功能研究表明，该突变不产生可证实的蛋白质，也没有转录活性或显性负效应。临床特征包括小睾丸发育不良，输精管和附睾，子宫缺如，阴道盲端，阴蒂肥大和性心理障碍。内分泌检查显示肾上腺功能正常（皮质醇对ACTH刺激的反应，13.4 -> 25.3 mug/dl）和原发性性腺功能减退症（睾酮对hCG刺激的反应，0.57 -> 0.76 ng/ml;促性腺激素对GnRH刺激的反应：LH，10 -> 59 mIU/ml; FSH，36 -> 69 mIU/ml）和尿类固醇激素谱分析表明类固醇生成酶活性大体正常。结果表明，SF-1单倍不足可以选择性地损害睾丸发育，并允许AMH和睾酮的生物合成在发育不良的睾丸和垂体促性腺激素的促性腺激素的生产。
Steroidogenic factor-1 (SF-1) regulates multiple genes involved in the adrenal and gonadal development and in the biosynthesis of a variety of hormones, including adrenal and gonadal steroids, anti-Mullerian hormone (AMH), and gonadotropins. We identified a novel SF-1 mutation in a 27-yr-old Japanese patient with a 46, XY karyotype. Sequence analysis was performed for all the seven exons of SF-1, revealing a heterozygous single base pair deletion at exon 2 (18delC) that is predicted to cause a frameshift at the sixth codon and resultant termination at the 74th codon. Functional studies showed that the mutation produced no demonstrable protein and had no transcription activity or dominant negative effect. Clinical features included small dysgenetic testes with vasa deferentia and epididymides, absent uterus, blind-ending vagina, clitoromegaly, and psychosexual disturbance. Endocrine studies showed normal adrenal function ( cortisol response to ACTH stimulation, 13.4 --> 25.3 mug/dl) and primary hypogonadism ( testosterone response to hCG stimulation, 0.57 --> 0.76 ng/ml; gonadotropin responses to GnRH stimulation: LH, 10 --> 59 mIU/ml; FSH, 36 --> 69 mIU/ml), and urinary steroid hormone profile analysis indicated grossly normal steroidogenic enzyme activities. The results suggest that SF-1 haploinsufficiency can selectively impair testicular development and permit the biosynthesis of AMH and testosterone in dysgenetic testes and the production of gonadotropins in pituitary gonadotropes.