Research on the transcriptional regulation of human Ad4BP gene and its related diseases

Ad 4 BP（SF-1）不仅是一种类固醇激素组织转录因子，而且对下丘脑-垂体-肾上腺和性腺轴的发育也是非常重要的。我们最近阐明了人Ad 4 BP基因的结构。通过对人Ad 4 BP基因5 ′-侧翼区的缺失分析，我们阐明了E-box对该基因的基础转录活性是非常必要的，这在其他物种中也有报道。Ad 4 BP破坏的小鼠没有其正常的肾上腺和性腺，以及在垂体中的促性腺激素特异性标记物的选择性损失。最近，一种新的核激素受体基因DAX-1从Xp 21区域中分离出来，并显示在X连锁先天性肾上腺发育不全（AHC）和低促性腺激素性性腺功能减退症（HHG）患者中发生致命性突变。我们还在几个这样的患者中发现了一些突变。然而，AHC和HHG的特殊病例，如女性患者和常染色体隐性遗传患者的分子基础尚不清楚。在这方面，我们分析了3例临床怀疑患有AHC和HHG的女性患者的Ad 4 BP基因，但在所有3例病例中均未发现突变。这一结果可能提示存在不同的常染色体基因。

Ad4BP (SF-1) is not only a steroidogenic tissue transcriptional factor but also be very essential for the development of a functioning hypothalamus-pituitary-adrenal and gonadal axis. We recently clarified a structure of human Ad4BP gene. Fom the deletion analysis of the 5'-flanking region of human Ad4BP gene, we clarified that E-box is very essential for the basal transcriptional activity of this gene, as also reported in other species. The Ad4BP-desrupted mouse was devoid of its normal adrenal glands and gonads as well as a selective loss of gonadotropin-specific markers in the pituitary. Recently, a new nuclear hormone receptor gene, DAX-1 was isolated from the Xp21 region and was shown to be fatally mutated in patients with X-linked adrenal hypoplasia congenita (AHC) and hypogonadotropic hypogonadism (HHG). We also identified some mutations in several such patients. However, the molecular basis of exceptional cases with AHC and HHG,such as female patients and patients with autosomal recessive inheritance remains unclear. In this respect, we analyzed the Ad4BP genes of three female patients who were clinically suspected to have AHC and HHG,but no mutations were found in all three cases. The result may suggest an existence of different autosomal gene responsible for this phenoytpe.