Functional characterization of a new human Ad4BP/SF-1 variation, G146A
Functional characterization of a new human Ad4BP/SF-1 variation, G146A
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DOI：
10.1016/j.bbrc.2003.10.096
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发表时间：
2003-11-28
影响因子：
3.1
通讯作者：
Nawata, H
中科院分区：
文献类型：
--
作者：
Fan, WQ;Yanase, T;Nawata, H
腺病毒4 BP/SF-1在下丘脑-垂体-类固醇器官轴的各个水平发挥关键作用，其功能中断导致这些器官的内分泌紊乱。然而，迄今为止，只有3例人类受试者报告了Ad 4 BP/SF-1突变，表明作为先天性肾上腺或性异常的原因的临床意义有限。我们报告的第一个功能特性的一个新的变化，发现在人类Ad 4 BP/SF-1，G146 A铰链区。G146 A的转录激活活性由于一个核苷酸的移位（GGG -> GCG）而略有降低，这一点可以通过肾上腺特异性cyp 11 A启动子和卵巢特异性cyp 19启动子II来证明。该变异不影响蛋白质表达或稳定性，未表现出显性负效应。G146 A与标准辅助调节因子具有正常的相互作用模式和亚核分布模式，并且可以被认为是非同义单核苷酸多态性，因为它发生在正常人和肾上腺疾病患者中。在正常日本人中，等位基因C的频率为8%，而在肾上腺疾病患者的初步人群中，该频率升高至30%;这表明G146 A变异可能具有临床意义。(C)2003年爱思唯尔公司All rights reserved.
Ad4BP/SF-1 plays key roles at all levels of the hypothalamic-pituitary-steroidogenic organ axis and its functional disruption causes endocrine disorders of these organs. However, only three human subjects with Ad4BP/SF-1 mutations have been reported to date, suggesting limited clinical significance as a cause of inborn adrenal or sexual abnormalities. We report the first functional characterization of a new variation found in the hinge region of human Ad4BP/SF-1, G146A. Resulting from a single nucleotide shift (GGG --> GCG), G146A bears slightly diminished transactivation activity evidenced by both adrenal specific cyp11A promoter and ovary specific cyp19 promoter II. The variation does not affect protein expression or stability, exhibiting no dominant negative effect. G146A has a normal interaction pattern with standard co-regulators and subnuclear distribution pattern, and can be considered as a nonsynonymous single nucleotide polymorphism, since it occurs in normals and patients with adrenal diseases. In normal Japanese the allele C frequency is 8%, while in a preliminary population of patients with adrenal diseases it is elevated to 30%; suggesting the G146A variation might be of clinical importance. (C) 2003 Elsevier Inc. All rights reserved.