Tsigos C, Tsiotra P, Garibaldi L R, Stavridis J C, Chrousos G P, Raptis S A
Hellenic National Diabetes Center (HNDC), Athens, Greece.
Mol Genet Metab. 2000 Dec;71(4):646-50. doi: 10.1006/mgme.2000.3090.
Isolated glucocorticoid deficiency (IGD) is an autosomal recessive disorder characterized by primary adrenocortical insufficiency, without mineralocorticoid deficiency. Mutations of the ACTH receptor gene have been reported in several families with IGD. We have amplified and directly sequenced the entire intronless ACTH receptor gene in a new family with IGD. The proband was found to be compound heterozygote for two different point mutations, one in each allele: (a) a substitution (360C>G) which changed neutral serine at position 120 in the apolar third transmembrane domain of the receptor to a positively charged arginine (S120R), probably disrupting the ligand-binding site; and (b) a substitution (761A>G) changing tyrosine at position 254 to cysteine (Y254C) in the third extracellular loop of the receptor protein, that also likely disrupts its structure and interferes with ligand binding. Each of the two mutations in the proband has previously been described in a different family, S120R in compound heterozygosity with a stop codon (R201X) and Y254C in homozygote form. Thus, in the absence of in vitro functional studies, our findings confirm the pathogenetic role of the S120R and Y254C mutants in the development of resistance to ACTH.
孤立性糖皮质激素缺乏症（IGD）是一种常染色体隐性疾病，其特征为原发性肾上腺皮质功能不全，而无盐皮质激素缺乏。在几个患有IGD的家族中已报道了促肾上腺皮质激素（ACTH）受体基因的突变。我们对一个患有IGD的新家族中的整个无内含子ACTH受体基因进行了扩增和直接测序。先证者被发现为两个不同点突变的复合杂合子，每个等位基因各有一个突变：（a）一个替换（360C>G），该替换将受体非极性第三个跨膜结构域中第120位的中性丝氨酸变为带正电荷的精氨酸（S120R），可能破坏了配体结合位点；（b）一个替换（761A>G），将受体蛋白第三个细胞外环中第254位的酪氨酸变为半胱氨酸（Y254C），这也可能破坏其结构并干扰配体结合。先证者中的这两个突变此前已在不同家族中被描述过，S120R与一个终止密码子（R201X）呈复合杂合状态，Y254C为纯合子形式。因此，在缺乏体外功能研究的情况下，我们的发现证实了S120R和Y254C突变体在对ACTH产生抗性的过程中的致病作用。
