MOLECULAR BIOLOGY OF PITUITARY GLYCOPROTEIN HORMONES & HYPOTHALAMIC HORMONES

我们已经克隆了几种人类脑下垂体糖蛋白激素的基因， 以及下丘脑释放激素，包括β亚基 人促甲状腺激素、人促甲状腺激素原原和人 促性腺激素释放激素。人类促甲状腺激素β亚基基因 我们已经将一种主要的甲状腺激素抑制因子定位在第一个 用扫描突变相结合的方法检测该基因的未翻译外显子 分析以及DNA、DNase I足迹与 亲和素-生物素复合体DNA结合。这种抑制因素似乎是 由两个不同的半位点组成，其中一个位于外显子的5‘端 另一个在外显子3‘端。这些不同的结果表明 甲状腺激素受体在第一阶段至少与两个部位结合 外显子协同介导T3抑制TSH-β的表达。我们 目前正试图定位负责抑制T3的区域 人类前TRH基因的表达，似乎位于5‘端 侧翼区域从-900到+54。人促甲状腺激素原前体的编码区 促性腺激素释放激素基因已经完全阐明。 发现前一个下丘脑激素基因有6个重复编码 TRH的序列不同于低等物种的数量。人类 促性腺激素释放激素基因被发现含有DNA序列 在转录起始点下游，增强了在 启动子特异性和位置依赖的方式。最后，用一本小说 促性腺激素释放激素DNA序列的多态性 基因，我们已经在一个家族性中枢性早熟的家庭中发现， 以及另一个患有特发性低促性腺激素减退症的家庭 这些情况与这一疾病的根本异常无关 吉恩。这种多态可能会被证明在评估与 GnRH基因在其他患有这种疾病的家族中的表达。这些研究还将 引起人们注意男性青春期功能异常的其他机制 与GnRH基因没有直接关联。

We have cloned the genes for several human pituitary glycoprotein hormones, as well as hypothalamic releasing hormones, including the beta subunit of human thyrotropin, as well as human prepro-TRH and human gonadotropin-releasing hormone. For the human thyrotropin beta subunit gene we have localized a major thyroid hormone inhibitory element in the first untranslated exon of this gene using a combination of scanning mutational analysis as well as DNA, DNase I footprinting in conjunction with avidin-biotin complex DNA binding. This inhibitory element appeared to be comprised of two distinct half-sites, one located at the 5' end of the exon and another toward the 3' end of the exon. These various results suggest that thyroid hormone receptors binding to at least two sites in the first exon act in conjunction to mediate T3 inhibition of TSH-beta expression. We are currently trying to localize the regions responsible for T3 inhibition of human prepro-TRH gene expression, which seems to be located in the 5' flanking region from -900 to +54. The coding regions of human prepro-TRH and gonadotropin-releasing hormone genes have been completely elucidated. The former hypothalamic hormone gene was found to have 6 repetitive coding sequences for TRH which differs from the number in lower species. The human gonadotropinreleasing hormone gene was found to contain DNA sequences downstream from the transcriptional start site that enhanced expression in a promoter-specific and position-dependent manner. Finally, using a novel polymorphism in the DNA sequence of the gonadotropin-releasing hormone gene, we have shown in a family familial central precocious puberty, as well as in another family with idiopathic hypogonadotropic hypogonadism that these conditions were not related to a fundamental abnormality in this gene. This polymorphism may prove useful in the evaluation of linkage to the GnRH gene in other families with this disorder. These studies will also draw attention to other mechanisms for abnormal pubertal function in man not directly associated with the GnRH gene.