Aalbers Anna M, Chin Daisy, Pratt Katherine L, Little Brian M, Frank Stuart J, Hwa Vivian, Rosenfeld Ron G
Department of Pediatrics, Oregon Health & Science University, Portland, OR 97239-3098, USA.
Horm Res. 2009;71(5):276-84. doi: 10.1159/000208801. Epub 2009 Apr 1.
BACKGROUND/AIMS: Circulating growth hormone-binding protein (GHBP), in humans, is the proteolytic product of the growth hormone receptor (GHR). We investigated a prepubertal male subject who was of short stature, but who had a markedly elevated serum level of GHBP.
Serum and DNA from the patient and his mother were analyzed.
Both the patient and mother had serum GHBP concentrations over 100-fold higher than normal, by assays, and Western and ligand blot analysis. Sequencing of the GHR gene revealed a novel heterozygous C>A transversion at position 785-3 in the acceptor splice site of intron 7.
In silico analysis of the altered sequence suggested that 785-3(C>A) is a splicing mutation, with either retention of intron 7 or the skipping of exon 8. The consequence is a truncated GHR lacking the transmembrane domain (encoded by exon 8) and the cytoplasmic domain. We hypothesize that this GHR variant cannot anchor to the cell membrane, and the continual secretion into the circulation explains the elevated levels of serum GHBP detected in the patient and his mother. Despite this mutation, the presence of the wild-type GHR allele, presumably, permits some normality in GH-induced action.
背景/目的：在人类中，循环生长激素结合蛋白（GHBP）是生长激素受体（GHR）的蛋白水解产物。我们研究了一名青春期前男性受试者，他身材矮小，但血清GHBP水平显著升高。
对患者及其母亲的血清和DNA进行了分析。
通过检测、蛋白质免疫印迹和配体印迹分析，患者及其母亲的血清GHBP浓度均比正常水平高出100倍以上。GHR基因测序显示，在第7内含子的受体剪接位点785-3处存在一种新的杂合C>A颠换。
对改变后的序列进行电子分析表明，785-3（C>A）是一种剪接突变，要么保留第7内含子，要么跳过第8外显子。结果是产生了一种截短的GHR，缺乏跨膜结构域（由第8外显子编码）和细胞质结构域。我们推测这种GHR变体无法锚定在细胞膜上，持续分泌到循环系统中解释了在患者及其母亲中检测到的血清GHBP水平升高。尽管存在这种突变，但野生型GHR等位基因的存在可能使GH诱导的作用具有一定的正常性。
