HEREDITARY ISOLATED GLUCOCORTICOID DEFICIENCY IS ASSOCIATED WITH ABNORMALITIES OF THE ADRENOCORTICOTROPIN RECEPTOR GENE
HEREDITARY ISOLATED GLUCOCORTICOID DEFICIENCY IS ASSOCIATED WITH ABNORMALITIES OF THE ADRENOCORTICOTROPIN RECEPTOR GENE
复制标题
DOI：
10.1172/jci116853
复制
发表时间：
1993-11-01
影响因子：
15.9
通讯作者：
CHROUSOS, GP
中科院分区：
文献类型：
--
作者：
TSIGOS, C;ARAI, K;CHROUSOS, GP
孤立性糖皮质激素缺乏症（IGD）是一种常染色体隐性遗传病，以进行性原发性肾上腺功能不全为特征，无糖皮质激素缺乏症。最近克隆了人ACTH受体的cDNA和基因。该基因编码一个297个氨基酸的蛋白质，属于膜受体的G蛋白偶联超家族。我们推测促肾上腺皮质激素受体基因可能在IGD中存在缺陷。为了检验这一点，我们通过PCR和直接测序研究了一个5岁的患病先证者、他的父母和祖父母的基因组结构。先证者是两个不同点突变的复合杂合子，每个等位基因上各有一个突变：(a)在母亲和外祖母的一个等位基因上也发现了一个替换（C—> T），该替换在蛋白201位引入了一个过早终止密码子（TGA）；这种突变受体缺乏其整个羧基末端，如果表达，应该不能转导信号；(b)在一个父本等位基因中也发现了一个取代（C—> G），它将受体极性第三跨膜区域的中性丝氨酸120改变为带正电的精氨酸，可能破坏了配体结合位点。标准的羊促肾上腺皮质激素释放激素（oCRH）试验在杂合子父母和外祖母中显示ACTH反应过度和延长，提示ACTH亚临床抵抗。我们的结论是，这个家族的IGD似乎是由于ACTH受体基因的缺陷。在确定这种综合征的杂合性时，oCRH试验似乎是有用的。
Isolated glucocorticoid deficiency (IGD) is an autosomal recessive disorder characterized by progressive primary adrenal insufficiency, without mineralocorticoid deficiency. The cDNA and gene of the human ACTH receptor were recently cloned. The gene encodes a 297-amino acid protein that belongs to the G protein-coupled superfamily of membrane receptors. We hypothesized that the ACTH receptor gene might be defective in IGD. To examine this, we studied its genomic structure by PCR and direct sequencing in a 5-yr-old proband with the disease, his parents, and grandparents. The proband was a compound heterozygote for two different point mutations, one in each allele: (a) a substitution (C --> T), also found in one allele of the mother and maternal grandmother, which introduced a premature stop codon (TGA) at position 201 of the protein; this mutant receptor lacks its entire carboxy-terminal third and, if expressed, should be unable to transduce the signal; and (b) a substitution (C --> G), also found in one of the paternal alleles, which changed neutral serine120 in the apolar third transmembrane domain of the receptor to a positively charged arginine, probably disrupting the ligand-binding site. Standard ovine corticotropin releasing hormone (oCRH) test in the heterozygote parents and maternal grandmother revealed exaggerated and prolonged ACTH responses, suggestive of subclinical resistance to ACTH. We conclude that IGD in this family appears to be due to defects of the ACTH receptor gene. The oCRH test appears to be useful in ascertaining heterozygosity in this syndrome.