Genetics of growth hormone gene expression.
Genetics of growth hormone gene expression.
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生长激素基因表达的遗传学。
DOI：
10.1159/000183768
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发表时间：
1993
期刊：
影响因子：
--
通讯作者：
Brown,MR
中科院分区：
文献类型：
--
作者：
Parks,JS;Abdul-Latif,H;Kinoshita,E;Meacham,LR;Pfaffle,RW;Brown,MR
垂体GH基因表达的调控依赖于转录激活蛋白与GH-1基因前的激活DNA序列的结合。POU同源结构域蛋白Pit-1存在于生长营养、乳营养和甲状腺营养细胞的细胞核中。它促进这些垂体细胞类型的分化，是成熟细胞产生激素所必需的。理论上，GH分泌缺陷可能是由GH-1启动子序列或编码Pit-1基因的突变引起的。在前一种情况下，缺乏将仅限于生长激素，而在后者的缺陷扩大到催乳素（Prl）和促甲状腺素（TSH）以及生长激素。Pit-1基因和GH-1基因已经在极度生长衰竭的儿童中进行了检测。对GH， Prl和TSH缺乏症的研究揭示了Pit-1基因的多种突变。这些突变包括无义突变，减少结合和转录激活的错义突变，以及似乎增加启动子结合而消除转录激活的突变。后一类突变在体内和体外都有主要的负面影响。在GH-1编码序列中有许多缺失的例子。有些非常大，导致GH-1、绒毛膜促生长激素和胎盘GH基因的丢失。其他的则很小，只涉及1到2个碱基。它们会产生帧移和过早停止信号。所有类型都产生生长激素完全缺乏，但在治疗期间抗体的发展已被证明是相当可变的。gh释放激素受体的cDNA最近被克隆和测序。它是导致孤立生长激素缺乏症的突变的主要候选基因。基础科学水平的进一步进展将提出其他候选基因，这些基因的破坏可能解释更常见的多种垂体激素缺乏症，包括GH、TSH、促肾上腺皮质激素和促性腺激素，但不包括Prl。
The regulation of pituitary GH gene expression depends on binding of transcriptional activation proteins tocis-active DNA sequences preceding the GH-1 gene. The POU homeodomain protein Pit-1 is found in the nuclei of somatotrophs, lactotrophs and thyrotrophs. It fosters differentiation of these pituitary cell types and is required for hormone production by mature cells. In theory, defects in GH secretion can be caused by mutations in the GH-1 promoter sequence or in the gene encoding Pit-1. In the former case, deficiency would be limited to GH, and in the latter deficiencies extend to prolactin (Prl) and thyrotropin (TSH) as well as to GH. Both the Pit-1 gene and the GH-1 gene have been examined in children with extreme growth failure. Studies of kindreds with GH, Prl and TSH deficiency have disclosed a variety of mutations in the Pit-1 gene. These include nonsense mutations, missense mutations that diminish binding and transcriptional activation, and also mutations that appear to increase promoter binding while eliminating transcriptional activation. This latter class of mutation exerts a dominant negative effect in vivo as well as in vitro. There are many examples of deletions in the GH-1 coding sequence. Some are very large and cause the loss of GH-1, chorionic somatomammotropin and placental GH genes. Others are very small, involving only 1 or 2 bases. They produce frameshifts and premature stop signals. All types produce complete deficiency of GH, but antibody development during treatment has proven to be quite variable. The cDNA for the GH-releasing hormone receptor has recently been cloned and sequenced. It is a leading candidate gene for mutations that cause isolated GH deficiency. Additional advances at the basic science level will bring forward other candidate genes whose disruption may account for more common forms of multiple pituitary hormone deficiency involving GH, TSH, adrenocorticotropin and gonadotropins, but not Prl.