[Mutations of ACTH receptor gene and familial syndrome of glucocorticoid deficiency]

Abstract

Familial isolated glucocorticoid deficiency syndrome is characterized by low cortisol plasma levels despite high ACTH levels without any stimulation of steroid production after ACTH administration. However, the mineralocorticoid function is well-preserved in this syndrome which indicates a specific resistance to ACTH. Recent cloning of the ACTH receptor allowed to study this receptor in this particular syndrome. After studying sixteen affected families, we have found three mutations in two patients from non-related families. One of these patients was a double heterozygote compound (C251F, G217fs) while the other one was homozygote for another mutation D107N. The mutant receptors were expressed in vitro in transfected M3 cells (S91 Cloudman cells) which represents a working expression system to express the ACTH receptor. Production of intracellular cyclic AMP was calculated in the presence of increasing concentrations of ACTH. The EC50 values were estimated (C251F: 3.5 +/- 0.9 x 10(-9) M, D107N: 3.0 +/- 0.9 x 10(-9) M, G217fs: 4.8 +/- 0.9 x 10(-9) M) and comparison with the value obtained for the wild type ACTH receptor (5.1 +/- 0.9 x 10(-10) M) indicates a clear 6 to 9 shift to the right due to an impaired function of these mutant receptors. Such results were expected for the G217fs mutation, and could be explained by a decrease in ligand affinity or an impaired coupling to adenylate cyclase in the case of amino acid substitutions. A total of twelve mutations has been described in the literature although eight of them have not been tested in vitro until now.