ACTH RECEPTOR GENE-MUTATIONS AND HEREDITA RY GLUCOCORTICOID DEFICIENCY

Familial isolated glucocorticoid deficiency syndrome is characterized by low cortisol plasma levels despite high ACTH levels without any sti mulation of steroid production after ACTH administration. However, the mineralocorticoid function is well-preserved in this syndrome which i ndicates a specific resistance to ACTH. Recent cloning of the ACTH rec eptor allowed to study this receptor in this particular syndrome. Afte r studying sixteen affected families, we have found three mutations in two patients from non-related families. One of these these patients w as a double heterozygote compound (C251F, G217fs) while the other one was homozygote for another mutation D107N. The mutant receptors were e xpressed in vitro in transfected M3 cells (S91 Cloudman cells) which r epresents a working expression system to express the ACTH receptor Pro duction of intracellular cyclic AMP was calculated In the presence of increasing concentrations of ACTH. The EC50 values were estimated (C25 1F : 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 r eceptors. Such results were expected for the G217fs mutation, and coul d be explained by a decrease in ligand affinity or an impaired couplin g to adenylate cyclase in the case of amino acid substitutions. A tota l of twelve mutations has been described in the literature although ei ght of them have not been tested in vitro until now.