Demonstration by transfection studies that mutations in the adrenocorticotropin receptor gene are one cause of the hereditary syndrome of glucocorticoid deficiency
Demonstration by transfection studies that mutations in the adrenocorticotropin receptor gene are one cause of the hereditary syndrome of glucocorticoid deficiency
复制标题
DOI：
10.1210/jc.81.4.1442
复制
发表时间：
1996-04-01
影响因子：
5.8
通讯作者：
Begeot, M
中科院分区：
文献类型：
--
作者：
Naville, D;Barjhoux, L;Begeot, M
ACTH无反应性遗传综合征是一种罕见的常染色体隐性遗传疾病，其特征是血清皮质醇水平低，血浆ACTH水平高。皮质醇对外源性ACTH无反应。最近克隆的人促肾上腺皮质激素受体基因，使我们能够研究这个基因在糖皮质激素缺乏症患者。通过PCR扩增ACTH受体基因的编码序列，我们在两个无关的患者中发现了三个突变。纯合形式中存在的一个突变将位于第三跨膜结构域中的（107）转化为不带电荷的Ash残基。第二个病人是一个复合杂合子：父亲的等位基因包含一个核苷酸插入导致终止密码子内的第三个细胞外环，和母亲的等位基因包含一个点突变转换Cys（251）苯丙氨酸，也在第三个细胞外环。在M3细胞系中表达正常和突变的ACTH受体基因，并测量响应于ACTH的细胞内cAMP产生。对于突变体受体，未检测到对生理ACTH浓度的响应，表明ACTH与受体的结合受损和/或与腺苷酸环化酶效应物的偶联改变。
The hereditary syndrome of unresponsiveness to ACTH is a rare autosomal recessive disorder characterized by low levels of serum cortisol and high levels of plasma ACTH. There is no cortisol response to exogenous ACTH. Recent cloning of the human ACTH receptor gene has enabled us to study this gene in patients with glucocorticoid deficiency. By using the PCR to amplify the coding sequence of the ACTH receptor gene, we identified three mutations in two unrelated patients. One mutation present in homozygous form converted the (107) located in the third transmembrane domain, to an uncharged Ash residue. The second patient was a compound heterozygote: the paternal allele contained a one-nucleotide insertion leading to a stop codon within the third extracellular loop, and the maternal allele contained a point mutation converting Cys(251) to Phe, also in the third extracellular loop. Normal and mutant ACTH receptor genes were expressed in the M3 cell line, and intracellular cAMP production in response to ACTH was measured. For the mutant receptors, no response to physiological ACTH concentrations was detected, suggesting an impaired binding of ACTH to the receptors and/or an altered coupling to the adenylate cyclase effector.