Heterozygous missense mutations in steroidogenic factor 1 (SF1/Ad4BP, NR5A1) are associated with 46,XY disorders of sex development with normal adrenal function.
Heterozygous missense mutations in steroidogenic factor 1 (SF1/Ad4BP, NR5A1) are associated with 46,XY disorders of sex development with normal adrenal function.
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类固醇生成因子1（SF1/AD4BP，NR5A1）中的杂合错义突变与46个，性别发展的XY疾病具有正常的肾上腺功能。
DOI：
10.1210/jc.2006-1672
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发表时间：
2007-03
期刊：
影响因子：
--
通讯作者：
Achermann JC
中科院分区：
文献类型：
--
作者：
Lin L;Philibert P;Ferraz-de-Souza B;Kelberman D;Homfray T;Albanese A;Molini V;Sebire NJ;Einaudi S;Conway GS;Hughes IA;Jameson JL;Sultan C;Dattani MT;Achermann JC
类固醇生成因子1（Steroidogenic factor 1，SF 1/AdBP 4/FTZF 1，NR 5A 1）是一种核受体转录因子，在调节肾上腺和性腺发育、类固醇生成和生殖中起关键作用。小鼠中Nr 5a 1（Sf 1）的靶向缺失导致雄性肾上腺和性腺发育不全、XY性逆转和持续性苗勒管结构。与鼠表型一致，SF 1的人类突变最初在两个46，XY个体中描述，这些个体具有女性外生殖器、苗勒氏结构（子宫）和原发性肾上腺衰竭。鉴于最近的SF 1单倍不足影响人类睾丸功能的病例报告，我们的目的是确定在一组具有46，XY性腺发育不全/雄激素化受损（现在称为46，XY性发育障碍，DSD）表型谱的肾上腺功能正常的个体中的SF 1突变。30例46，XY DSD患者的NR 5A 1突变分析，随后进行SF 1活性的功能研究。在4例（4/30，13%）具有该表型的个体中发现NR 5A 1杂合错义突变。这些突变（V15 M、M78 I、G91 S、L437 Q）显示通过异常DNA结合（V15 M、M78 I、G91 S）、改变的亚核定位（V15 M、M78 I）或通过破坏推定的配体结合口袋（L437 Q）来损害转录激活。两个突变似乎是从头或种系变化。另外两个突变似乎是以性别限制的显性方式遗传的，因为母亲是杂合子的变化。这些研究表明，SF 1突变比以前怀疑的46，XY个体胎儿和出生后睾丸功能受损的原因更常见。
Steroidogenic factor 1 (SF1/AdBP4/FTZF1, NR5A1) is a nuclear receptor transcription factor that plays a key role in regulating adrenal and gonadal development, steroidogenesis, and reproduction. Targeted deletion of Nr5a1 (Sf1) in the mouse results in adrenal and gonadal agenesis, XY sex-reversal, and persistent Müllerian structures in males. Consistent with the murine phenotype, human mutations in SF1 were described initially in two 46,XY individuals with female external genitalia, Müllerian structures (uterus) and primary adrenal failure. Given recent case reports of haploinsufficiency of SF1 affecting testicular function in humans, we aimed to identify SF1 mutations in a cohort of individuals with a phenotypic spectrum of 46,XY gonadal dysgenesis/impaired androgenization (now termed 46,XY Disorders of Sex Development, DSD) with normal adrenal function. Mutational analysis of NR5A1 in 30 individuals with 46,XY DSD, followed by functional studies of SF1 activity. Heterozygous missense mutations in NR5A1 were found in four individuals (4/30, 13%) with this phenotype. These mutations (V15M, M78I, G91S, L437Q) were shown to impair transcriptional activation through abnormal DNA binding (V15M, M78I, G91S), altered sub-nuclear localization (V15M, M78I), or through disruption of the putative ligand-binding pocket (L437Q). Two mutations appeared to be de novo or germline changes. The other two mutations appeared to be inherited in a sex-limited dominant manner, as the mother is heterozygous for the change. These studies demonstrate that SF1 mutations are more frequent than previously suspected causes of impaired fetal and postnatal testicular function in 46,XY individuals.
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影响因子：
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作者：
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DOI：
10.1046/j.1365-2710.2000.00313.x
发表时间：
2000-12-01
影响因子：
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通讯作者：
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