Mutations of the ACTH receptor gene in a new family with isolated glucocorticoid deficiency.

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.